Stigma in Pediatric Cancer: An Exploratory Study of Osteosarcoma and Retinoblastoma in Guatemala, Jordan, and Zimbabwe.

PURPOSE: Stigma is an understudied barrier to health care acceptance in pediatric oncology. We sought to explore the stigma experience, including its impact on cancer treatment decision making, and identify strategies to mitigate stigma for patients with osteosarcoma and retinoblastoma in Guatemala, Jordan, and Zimbabwe. METHODS: Participants included caregivers, adolescent patients (age 12-19 years), and health care clinicians. A semistructured interview guide based on The Health Stigma and Discrimination Framework (HSDF) was adapted for use at each site. Interviews were conducted in English, Spanish, Arabic, or Shona, audio-recorded, translated, and transcribed. Thematic analysis focused on stigma practices, experiences, outcomes, drivers, mitigators, and interventions. RESULTS: We conducted 56 interviews (28 caregivers, 19 health care clinicians, nine patients; 20 in Guatemala, 21 in Jordan, 15 in Zimbabwe). Major themes were organized into categories used to adapt the HSDF to global pediatric cancer care. Themes were described similarly across all sites, ages, and diagnoses, with specific cultural nuances noted. Pediatric cancer stigma was depicted as an isolating and emotional experience beginning at diagnosis and including internalized and associative stigma. Stigma affected decision making and contributed to negative outcomes including delayed diagnosis, treatment abandonment, regret, and psychosocial fragility. Overcoming stigma led to positive outcomes including resilience, treatment adherence, pride, and advocacy. Identified stigma drivers and mitigators were linked to potential interventions. CONCLUSION: Participants describe a shared stigma experience that transcends geography, cultural context, age, and diagnosis. Stigma manifestations have the potential to impact medical decision making and affect long-term psychological outcomes. Stigma assessment tools and interventions aimed at stigma mitigation including educational initiatives and support groups specific to pediatric cancer should be the focus of future research.

Expanding the Global Capacity for Childhood Cancer Registration: The ChildGICR Masterclass.

PURPOSE: One determinant of the paucity of data on childhood cancer in low- and middle-income countries is the lack of capacity to register these cases. Combining expertise of the Global Initiative for Cancer Registry Development (GICR) and St Jude Global, we developed a ChildGICR educational program to promote data production. METHODS: We first conducted a needs assessment to identify priority educational topics. Then, we designed the ChildGICR Masterclass, in which individuals with the potential to lead pediatric cancer registration were supported to prepare standard educational material. The outcomes were evaluated using qualitative and quantitative measures. RESULTS: On the basis of indications by 38 GICR collaborators, we identified seven topics relevant to childhood cancer: burden description, registration principles, tumor classification, tumor staging, data quality control, data analysis, and data use. The ChildGICR Masterclass was held online in 2021 over 12 weeks. The 22 nominated participants created presentations in working groups and during live sessions. They also designed future training courses tailored to the needs of their region. Nineteen participants viewed the course experience as excellent, and 20 would continue engagement in the ChildGICR training activities. The developed material was 89% useful according to the faculty of the three online end courses, taught to 88 participants in 16 countries in 2022 and 2023. Among the 75 responding participants, 72 agreed that the learning objectives were attained and 60 were keen to engage in childhood cancer registration activities. CONCLUSION: The ChildGICR Masterclass participants laid the foundation for a network of trainers. Knowledge dissemination in childhood cancer registration is the first necessary step toward evidence-based cancer control. The ChildGICR Masterclass can serve as a model to design, plan, and implement educational programs for health care professionals.

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.

Síndrome de burnout en cirujanos generales en tiempos de la pandemia COVID-19

Objetivo: Evaluar el síndrome de burnout (SB) en cirujanos generales. Material y Método: Se realizó un estudio de corte transversal en nuestro centro hospitalario, en agosto de 2021. La muestra estuvo formada por 56 profesionales de la salud que incluyeron a residentes y especialistas en cirugia general quienes prestaron servicio en el contexto de la COVID-19. Resultados: La prevalencia del burnout fue del 71%, la edad media fue de 34 años y los residentes fueron los más afectados (62,5%). La distribución por sexo fue de 82,5% en masculinos y 17,5% en el sexo femenino. Del total de evaluados, 23 son casados y 17 solteros, predominando los cirujanos con hijos (60%). Discusión: Entre los pocos estudios publicados sobre el SB en trabajadores de la salud en tiempos de COVID-19 se ubican como posibles factores predisponentes: a las privaciones de sueño, el riesgo biológico ocupacional intrínseco, la cuarentena obligada a la que tienen que someterse los trabajadores de la salud fuera de casa y los dilemas éticos en la toma de decisiones de atención a pacientes. Sin embargo, un estudio ha mostrado que los estresores vinculados al SB más importantes son la falta de equipo de protección personal, el miedo al contagio de COVID-19 y el miedo de contagiar a los familiares. Conclusión: Existe una alta prevalencia del SB en cirujanos generales en el contexto de la pandemia COVID-19. Los más afectados fueron residentes jóvenes de sexo masculino, casados, con hijos y con bajos ingresos económicos.

Objective: To evaluate the burnout syndrome (BS) in general surgeons. Material and Method: A cross-sectional study was carried out in our hospital in August 2021. The sample consisted of 56 health professionals that included residents and specialists in general surgery who provided service in the context of COVID-19 Results: The prevalence of burnout was 71%, the mean age was 34 years and the residents were the most affected (62.5%). Sex was 82.5% in males and 17.5% in females. Of the total evaluated, 23 are married and 17 are single, with a predominance of surgeons with children (60%). Discussion: Among the few studies published on BS in health workers in times of COVID-19, the following are located as possible predisposing factors: sleep deprivation, intrinsic occupational biological risk, the forced quarantine that patients have to undergo. out-of-home health workers and ethical dilemmas in patient care decision-making. However, a study has shown that the most important stressors linked to BS are the lack of personal protective equipment, the fear of contagion of COVID-19 and the fear of infecting family members. Conclusion: There is a high prevalence of BS in general surgeons in the context of the COVID-19 pandemic. The most affected were young male residents, married, with children and with low income.

Health Equity in Pediatric Drug Development: Translating Aspiration into Operation.

The concept of health equity-the attainment of the highest possible level of health for all members of society-requires equitable access to all aspects of healthcare, including pediatric drug development. However, many communities are under-represented in pediatric drug development programs. Barriers to participation include geographic, economic, racial/ethnic bias, legal, cultural, linguistic, and other factors. While there is no "one size fits all" approach to addressing these barriers, community engagement and collaboration is recognized by the Centers for Disease Control, the World Health Organization, and other global health organizations as a cornerstone for building a more equitable healthcare system. In this article, we will present case studies of stakeholder and community engagement in clinical research for rare diseases and other areas of healthcare, as examples of strategies and practices for actively involving under-represented communities and fostering their participation in pediatric drug development programs. These studies may serve as templates for facilitating equity in pediatric drug development from aspiration into operation.

Risk factors associated with metastatic site failure in patients with high-risk neuroblastoma.

Purpose: This retrospective study sought to identify predictors of metastatic site failure (MSF) at new and/or original (present at diagnosis) sites in high-risk neuroblastoma patients. Methods and materials: Seventy-six high-risk neuroblastoma patients treated on four institutional prospective trials from 1997 to 2014 with induction chemotherapy, surgery, myeloablative chemotherapy, stem-cell rescue, and were eligible for consolidative primary and metastatic site (MS) radiotherapy were eligible for study inclusion. Computed-tomography and I-123 MIBG scans were used to assess disease response and Curie scores at diagnosis, post-induction, post-transplant, and treatment failure. Outcomes were described using the Kaplan-Meier estimator. Cox proportional hazards frailty (cphfR) and CPH regression (CPHr) were used to identify covariates predictive of MSF at a site identified either at diagnosis or later. Results: MSF occurred in 42 patients (55%). Consolidative MS RT was applied to 30 MSs in 10 patients. Original-MSF occurred in 146 of 383 (38%) non-irradiated and 18 of 30 (60%) irradiated MSs (p = 0.018). Original- MSF occurred in post-induction MIBG-avid MSs in 68 of 81 (84%) non-irradiated and 12 of 14 (85%) radiated MSs (p = 0.867). The median overall and progression-free survival rates were 61 months (95% CI 42.6-Not Reached) and 24.1 months (95% CI 16.5-38.7), respectively. Multivariate CPHr identified inability to undergo transplant (HR 32.4 95%CI 9.3-96.8, p < 0.001) and/or maintenance chemotherapy (HR 5.2, 95%CI 1.7-16.2, p = 0.005), and the presence of lung metastases at diagnosis (HR 4.4 95%CI 1.7-11.1, p = 0.002) as predictors of new MSF. The new MSF-free survival rate at 3 years was 25% and 87% in patients with and without high-risk factors. Conclusions: Incremental improvements in systemic therapy influence the patterns and type of metastatic site failure in neuroblastoma. Persistence of MIBG-avidity following induction chemotherapy and transplant at MSs increased the hazard for MSF.

Longer summer seasons after fire induce permanent drought legacy effects on Mediterranean plant communities dominated by obligate seeders.

The ecological stability of Mediterranean ecosystems is being threatened by climate change. One of the impacts that is expected to be aggravated is the effect of summer drought prolongation toward previous or subsequent seasons by becoming more frequent. This, along with wildfires, could trigger synergistic negative effects on ecosystem regeneration capacity. Here we assessed how extending summer drought in two different ways (to autumn, AutExcl treatment, or bringing it forward to the following spring, SprExcl treatment) would affect plant recovery after an experimental fire carried out in summer in a Mediterranean seeder community. By installing rainout shelters, we assessed differences in seedling emergence, survival and establishment in the main families (Cistaceae, Labiatae, Leguminosae), and the effect on species richness and community composition. We observed that these post-fire dry season extensions reduced the total number of established seedlings and species richness. The most impacting drought treatment was AutExcl. However, the regeneration response was variable depending on the studied family. SprExcl was also determinant for Labiate survival rates. These results suggest that drought events which prolong the usual summer season may have a permanent drought legacy effect on seeder communities as practically all the seeder species populations were established in the first post-fire year. This fact is relevant for Mediterranean ecosystems dominated by seeder species as severer and longer droughts are increasingly recorded and are expected to become more frequent in forthcoming decades.

Limited contribution of post-fire eco-engineering techniques to support post-fire plant diversity.

Eco-engineering techniques are generally effective at reducing soil erosion and restore vegetal cover after wildfire. However, less evidence exists on the effects of the post-fire eco-engineering techniques to restore plant diversity. To fill this knowledge gap, a standardized regional-scale analysis of the influence of post-fire eco-engineering techniques (log erosion barriers, contour felled log debris, mulching, chipping and felling, in some cases with burning) on species richness and diversity is proposed, adopting the Iberian Peninsula as case study. In general, no significant differences in species richness and diversity (Shannon) were found between the forest treated with different post-fire eco-engineering techniques, and the burned and non-treated soils. Only small significant differences were found for some sites treated with log erosion barriers or mulching. The latter technique increased species richness and diversity in some pine species and shrublands. Contour felled log debris with burning slightly increased vegetation diversity, while log erosion barriers, chipping and felling were not successful in supporting plant diversity. This research will help forest managers and agents in Mediterranean forest to decide the best postfire management option for wildfire affected forest, and in the development of more effective post-fire strategies.

Thinning and plantation of resprouting species redirect overstocked pine stands towards more functional communities in the Mediterranean basin.

Post-fire regeneration in Pinus halepensis' forests, one of the most abundant vegetation types in the Mediterranean basin, often generates overstocked and vulnerable stands. They accumulate a high fuel load, increasing the risk of further fires, and present high levels of vulnerability due to their reduced seed production. In addition, these dense stands substantially reduce the availability of light and nutrients, which may hinder the recruitment of other species, often generating mono-specific and homogeneous stands, which potentially supply fewer ecosystem services than mixed forests with more heterogeneous structures. In these dense pine stands, management is of high priority to reduce fire hazards and promote their functionality. In overstocked pine stands (>75,000 trees·ha-1), we assessed the long-term effects (10 years) of two thinning levels (600 and 1200 trees·ha-1), in combination with the plantation of Quercus faginea (a resprouter species typical of advanced successional stages in our study area) on 28 above and belowground ecosystem attributes, including fire hazard. After ten years, thinning and plantation interacted to enhance ecosystem attributes associated with disturbance regulation and biodiversity conservation (up to 200%) and food production (up to 90%), while no effects were observed on those attributes related to carbon sequestration and supporting services. These effects were mainly driven by aboveground attributes, as they responded more strongly to our treatments than those belowground. Our results are relevant for the restoration of Mediterranean degraded ecosystems, and show that tree thinning in overstocked pine stands, combined with the plantation of resprouter species, may not only reduce fire risks and accelerate post-fire succession but also enhance the supply of multiple ecosystem services in the long run.

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 I trial of talazoparib and irinotecan with and without temozolomide in children and young adults with recurrent or refractory solid malignancies.

BACKGROUND: Talazoparib combined with irinotecan and temozolomide demonstrated efficacy in a murine Ewing sarcoma model. Based on these data, we conducted a phase I trial of talazoparib and irinotecan with/without temozolomide in paediatric patients with recurrent/refractory solid malignancies. PATIENTS AND METHODS: Cohorts of 3-6 patients with recurrent/refractory solid malignancies received escalating doses of oral talazoparib and intravenous irinotecan (arm A) and oral talazoparib, oral temozolomide and intravenous irinotecan (arm B) in a 3 + 3 design. Talazoparib was administered on days 1-6, and intravenous irinotecan and oral temozolomide were administered on days 2-6, of a 21-day course. Serum for talazoparib and irinotecan pharmacokinetics was obtained during course 1. UGT1A1 polymorphism and Schlafen family member 11 (SLFN11) immunohistochemical staining were performed. RESULTS: Forty-one patients (20 males; median age, 14.6 years; 24 with recurrent disease) were evaluable for dose escalation. Twenty-nine and 12 patients were treated on arm A and arm B, respectively, for a total of 208 courses. The most common diagnosis was Ewing sarcoma (53%). The most common ≥grade III haematologic toxicities in arms A and B included neutropenia (78% and 31%, respectively) and thrombocytopenia (42% and 31%, respectively). In arms A and B, febrile neutropenia (24% and 14%, respectively) and diarrhoea (21% and 7%, respectively) were the most common ≥grade III non-hematologic toxicities. Six patients (Ewing sarcoma [5 patients] and synovial sarcoma [1 patient]) had a response (1 with a complete response, 5 with a partial response). The objective response rates were 10.3% (arm A) and 25% (arm B). Pharmacokinetic testing demonstrated no evidence of drug-drug interaction between talazoparib and irinotecan. UGT1A1 was not related to response. SLFN11 positivity was associated with best response to therapy. CONCLUSIONS: The combination of talazoparib and irinotecan with/without temozolomide is feasible and active in Ewing sarcoma, and further investigation is warranted.

A Phase 1 and pharmacokinetic study evaluating daily or weekly schedules of the humanized anti-GD2 antibody hu14.18K322A in recurrent/refractory solid tumors.

Hu14.18K322A is a humanized anti-GD2 monoclonal antibody with a single point mutation that reduces complement-mediated cytotoxicity, with a maximum tolerated dose (MTD) of 60 mg/m2 daily for 4 days in children with recurrent/refractory neuroblastoma. We report additional results of a Phase 1 trial to determine the MTD and safety profile of hu14.18K322A in patients with osteosarcoma, and of an alternative schedule of weekly hu14.18K322A administration in patients with neuroblastoma or osteosarcoma. Eligible patients with recurrent/refractory osteosarcoma received hu14.13K22A daily x4 every 28 days in a Phase 1 traditional 3 + 3 dose escalation design. Additional patients with osteosarcoma were then enrolled to receive hu14.18K322A once weekly for 4 weeks per course. Patients with recurrent/refractory neuroblastoma were also enrolled on the weekly schedule at 50 mg/m2/dose. Six patients with osteosarcoma treated on the daily schedule received a median of 2 (range 1-6) courses; the recommended daily dose was established as 60 mg/m2. Three patients had stable disease (SD) as best overall response. Five patients (3 neuroblastoma, 2 osteosarcoma) enrolled on the weekly schedule received a median of 1 (1-3) course; 2 achieved SD as best overall response. Pain, fever, hematologic toxicities, hyponatremia, and ocular/visual abnormalities were common toxicities among both schedules. Dose-limiting toxicities attributed to hu14.18K322A included anorexia and fatigue (n = 1). Pharmacokinetic profiles were similar between daily and weekly schedules. The recommended dose for patients with osteosarcoma receiving daily hu14.18K322A x4 is 60 mg/m2. Patients receiving the weekly schedule experienced similar pharmacokinetics and toxicity profile as the daily schedule.

Phase I expansion cohort to evaluate the combination of bevacizumab, sorafenib and low-dose cyclophosphamide in children and young adults with refractory or recurrent solid tumours.

BACKGROUND: Angiogenesis is critical for tumour growth and metastasis. Dual inhibition of vascular endothelial growth factors and platelet-derived growth factor receptors suppresses angiogenesis. This expansion cohort of a phase I study targeted angiogenesis with sorafenib, bevacizumab and low-dose cyclophosphamide in children and young adults with recurrent solid tumours. METHODS: An expansion cohort including patients with refractory or recurrent solid tumours was enrolled and received bevacizumab (15 mg/kg IV, day 1), sorafenib (90 mg/m2 po twice daily, days 1-21) and low-dose cyclophosphamide (50 mg/m2 po daily, days 1-21). Each course was 21 days. Toxicities were assessed using Common Terminology Criteria for Adverse Events, v3.0, and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. Serial bevacizumab pharmacokinetic (PK) studies were performed during course 1. RESULTS: Twenty-four patients (15 males; median age 14.5 yrs; range 1-22 yr) received a median of 6 courses (range 1-18). Twelve patients had a bone or soft tissue sarcoma. The most common grade III/IV non-haematologic toxicities were hypertension (N = 4), hand/foot rash (N = 3) and elevated lipase (N = 3). The most common grade III/IV haematologic toxicities were neutropenia (N = 7) and lymphopenia (N = 17). Three patients (2 synovial sarcoma, 1 rhabdoid tumour) achieved a partial response and 18 had stable disease. The progression-free survival at 3 and 6 months were 78.1% (95% confidence interval [CI] 60.6-95.6%) and 54% (95% CI 30.2-78.2%), respectively. Bevacizumab PKs in 15 patients was similar to published adult PK results. CONCLUSIONS: Intravenous bevacizumab combined with oral sorafenib and low-dose cyclophosphamide was tolerated and demonstrated promising activity in a subset of childhood solid tumours.

Communication Regarding Therapeutic Clinical Trial Enrollment Between Oncologists and Adolescents and Young Adults with Cancer.

Adolescent and young adult (AYA) cancer patients enroll in therapeutic clinical trials at low rates. Prior study has focused on trial availability; this research attempts to elucidate the role of communication in individual decision-making. We surveyed 193 AYA patients and reviewed medical records of informed consent discussions. Twenty percent (38/193) of patients were offered trials, 58% (22/38) enrolled. Many were unable to correctly identify whether they were offered trials or enrolled, including 27% (6/22) of patients on clinical trials who believed that they were not. Efforts to improve communication have potential to enhance informed decision-making in this vulnerable population.

Fire regimes shape diversity and traits of vegetation under different climatic conditions.

Changes in climate and land use are altering fire regimes in many regions across the globe. This work aims to study the influence of wildfire recurrence and burn severity on woody community structure and plant functional traits under different environmental conditions. We selected three study sites along a Mediterranean-Oceanic climatic gradient, where we studied the fire history and burn severity of the last wildfire. Four years after the last wildfire, we established 1776 1-m2 plots where the percentage cover of each woody species was sampled. We calculated (i) structural parameters of the community such as total cover, alpha species richness, evenness and diversity (Shannon diversity index), and (ii) vegetation cover of each functional group (differentiating life forms, eco-physiological traits and regenerative traits). Focusing on community structure, results showed increases in species richness and diversity as wildfire recurrence increased, but this effect was partially counterweighted in the areas affected by high severity. In relation to functional groups, we found that increases in recurrence and severity fostered transition from tree- to shrub-dominated ecosystems. Non-arboreal life form, high specific leaf area, N2-fixing capacity, resprouting ability and heat-stimulated germination were advantageous traits under high recurrences and severities, and low seed mass was advantageous under high recurrence situations. We suggest that the strength of the effects of wildfire recurrence and burn severity on vegetation structure and traits might vary with climate, increasing from Oceanic to Mediterranean conditions. In the Mediterranean site, recurrence and severity were strongly related to traits associated with germination (seed mass and heat-stimulated germination), whereas in the Oceanic site the strongest relationships were found with a resprouting-related trait (bud location). This study identifies changes in vegetation structure and composition in scenarios of high recurrence and severity, and provides useful information on plant traits that could be key in enhancing vegetation resilience.

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.

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.