Stage at diagnosis and survival by stage for the leading childhood cancers in Rwanda.

BACKGROUND: The lack of accurate population-based information on childhood cancer stage and survival in low-income countries is a barrier to improving childhood cancer outcomes. METHODS: In this study, data from the Rwanda National Cancer Registry (RNCR) were examined for children aged 0-14 diagnosed in 2013-2017 for the eight most commonly occurring childhood cancers: acute lymphoblastic leukaemia, Hodgkin lymphoma (HL), Burkitt lymphoma (BL), non-Hodgkin lymphoma excluding BL, retinoblastoma, Wilms tumour, osteosarcoma and rhabdomyosarcoma. Utilising the Toronto Childhood Cancer Stage Guidelines Tier 1, the study assigned stage at diagnosis to all, except HL, and conducted active follow-ups to calculate 1-, 3- and 5-year observed and relative survival by cancer type and stage at diagnosis. RESULTS: The cohort comprised 412 children, of whom 49% (n = 202) died within 5 years of diagnosis. Five-year survival ranged from 28% (95% confidence interval [CI]: 12.5%-45.6%) for BL to 68% (CI: 55%-78%) for retinoblastoma. For the cancers for which staging was carried out, it was assigned for 83% patients (n = 301 of 362), with over half (58%) having limited or localised stage at diagnosis. Stage was a strong predictor of survival; for example, 3-year survival was 70% (95% CI: 45.1%-85.3%) and 11.8% (2.0%-31.2%) for limited and advanced non-HL, respectively (p < .001). CONCLUSION: This study is only the second to report on stage distribution and stage-specific survival for childhood cancers in sub-Saharan Africa. It demonstrates the feasibility of the Toronto Stage Guidelines in a low-resource setting, and highlights the value of population-based cancer registries in aiding our understanding of the poor outcomes experienced by this population.

Trends in incidence and survival of childhood cancers in Khon Kaen, Thailand (2000-2019): a population-based Khon Kaen Cancer Registry study.

BACKGROUND: In Thailand, the national health care system and nationwide standard treatment protocols have evolved over time, potentially influencing the trends in the incidence and survival rates of childhood cancers. However, further investigations are required to comprehensively study these trends in Khon Kaen, Thailand. METHODS: Childhood cancer patients aged 0-14 years (n = 541) who were diagnosed with one of the five most common cancers between 2000 and 2019 from the population-based Khon Kaen Cancer Registry were enrolled. Descriptive statistics were used to analyse the demographic data, which are presented as numbers, percentages, means, and standard deviations. The trends in incidence between 2000 and 2019, including age-standardized incidence rates (ASRs) and annual percent changes (APCs), were analysed using the Joinpoint regression model. Survival analysis was performed for 5-year relative survival rates (RSRs) according to the Pohar Perme estimator and Kaplan-Meier survival curves. RESULTS: The ASRs of the overall top 5 childhood cancer groups were 67.96 and 106.12 per million person-years in 2000 and 2019, respectively. Overall, the APC significantly increased by 2.37% each year for both sexes. The overall 5-year RSRs were 60.5% for both sexes, 58.2% for males, and 63.9% for females. The highest 5-year RSR was for germ cell tumours (84.3%), whereas the lowest 5-year RSR was for neuroblastoma (29.1%). CONCLUSIONS: The incidence and survival rates of childhood cancers in Khon Kaen, Thailand, varied according to sex. The incidence trends increased over time, meanwhile, the relative survival rates rose to satisfactory levels and were comparable to those of other nations with similar financial status. The implementation of national health policies and adherence to national treatment guidelines have improved cancer diagnosis and treatment outcomes.

Noncompliance of pediatric cancer patients with chemotherapy: A single-center experience in a lower-middle income country.

Noncompliance with therapy is a big obstacle to successful therapy. We aimed to evaluate the prevalence and risk factors affecting the compliance of pediatric cancer patients with therapy in a tertiary care center far away from the capital in a lower-middle income country (LMIC). A retrospective cohort study of reports of all pediatric cancer patients who were diagnosed and started treatment between 2006 and 2010 at South Egypt Cancer Institute (SECI) was done. The following data were collected: Age, sex, diagnosis, compliance with therapy, and data on potential risk factors that might affect compliance, including time duration of travel from the patient's home to SECI, time lag between the first symptom until the first visit to SECI and until the start of treatment, results of reevaluation after the initial course of therapy, and therapy-related severe adverse events. Noncompliance with therapy was defined as when patients missed their determined therapy appointment for one week or more or abandoned therapy. This study included 510 patients. Eighty-three (16.3%) were non-compliant, as forty patients missed their therapy appointment (7.8%), and 43 abandoned further therapy (8.4%). Noncompliance was found to be more prevalent among patients with solid tumors. Non-compliant patients suffered a significantly higher relapse rate (47.7% vs. 11.2% in compliant patients, p < .001). Unfortunately, 75% of the abandoned patients who returned for further therapy suffered a relapse. Noncompliance with treatment is still a big problem facing cancer management in LMICs.

A retrospective review on the histopathological pattern of childhood malignant solid tumors in Ethiopia.

In low- and middle-income countries (LMICs), malignancies remain underreported due to lack of quality data. This study outlines the histopathological pattern of pediatric solid malignancies in children aged 0-15 years at the largest referral hospital in Ethiopia. A total of 432 solid malignancies were evaluated. The most common malignancies were lymphoma (21.8%), retinoblastoma (19.4%), and Wilms tumor (13.9%). Burkitt lymphoma accounted for 2.1%, despite being the most reported pediatric malignancy in sub-Saharan Africa in published literature. Definitive diagnosis could not be made in 7% of cases, related to the lack of confirmatory testing. The study highlights the need for improvement in diagnostic capabilities in LMICs.

The feasibility of implementing Toronto childhood cancer stage guidelines and estimating the impact on outcome for childhood cancers in seven pediatric oncology units in sub-Saharan Africa. A study from the Franco-African Pediatric Oncology Group.

BACKGROUND: The improvement of childhood cancer outcome is determined by early diagnosis, effective treatment, supportive care, and adequate medical follow-up. Stage at diagnosis may reflect timeliness of diagnosis, therefore standardized registration of stage is essential for interpretation of regional differences and time trends in survival. Here, we describe the feasibility of implementing the Toronto Childhood Cancer Stage Guidelines (hereafter Toronto Guidelines [TG]) in the hospital-based cancer registry of the Franco-African Pediatric Oncology Group (GFAOP), and assess the impact of TG stage on outcome in pediatric oncology units (POUs) in seven low- and middle-income countries in sub-Saharan Africa (SSA). METHODS: All cancer patients diagnosed before 15 years of age with one of the 15 cancer types defined in TG, resident in one of the participating countries, and attending one of the selected POUs in 2017-2019 were included. Stage was assigned according to TG. Patients were followed-up for vital status for at least 12 months post diagnosis. Survival at 3, 6, and 12 months was calculated using Kaplan-Meier method and compared between POUs and tumor groups using log-rank test. RESULTS: TG stage was assigned to 1772 of 2446 (89%) cases diagnosed with one of 11 cancer types. It was not possible to assign TG stage to acute lymphoblastic leukemia (ALL) and the three types of the central nervous system tumors included in the TG. One-year overall survival (OS) was 58% [95% confidence interval: 55-60] and varied between POUs. Survival declined with increasing stage for four tumor types and was statistically significant for two. CONCLUSION: Except for ALL and brain tumors, we demonstrated feasibility of TG implementation for childhood solid cancers in participating POUs in SSA, and provided a baseline assessment of childhood cancer outcomes against which future stage distribution and survival can be measured as timelines of diagnosis improve over time within the GFAOP network.

[Incidence of cancer among children and adolescents (0-19 years) in Lazio Region (Central Italy), 2009-2015]. / Incidenza di tumori nella popolazione infantile e adolescenziale (0-19 anni) della Regione Lazio, anni 2009-2015.

OBJECTIVES: to investigate, for the first time, the incidence of cancer (years 2009-2015) and geographical distribution among children and adolescents with cancer diagnosis in Lazio Region (Central Italy). DESIGN: to compute incidence rates of childhood cancers from Lazio Region Childhood Cancer Registry (LRCCR) database, established in 2015, and to compare results with national figures for 2012 provided by the Italian cancer registries network (AIRTUM). SETTING AND PARTICIPANTS: all new cases of malignant tumours (behaviour: /3 of ICD-O-3 classification) and all central nervous system tumours were selected, regardless of behaviour (/0, /1, /3) in children and adolescents (0-19 years) registered in the LRCCR data base. MAIN OUTCOME MEASURES: it was computed: • the raw and the direct standardised rates for the 0-14-year and the 15-19-year age groups for total malignant tumours of the ICCC-3 classification by area (province level and municipality of Rome); • Relative Risks (RR) for area-specific rate compared with that of the Lazio Region and 95% Confidence Intervals (95%CI). RESULTS: a total of 1,782 incident cases were recorded in 2009-2015; of these, 91.4% were confirmed by a pathology report. Standardized Incidence Rate for all malignant tumours is 207.2×1,000,000 (95%CI 195.5-219.5) in children and 335.1×1,000,000 (95%CI 308.9-361.2) in adolescents. Compared to the Lazio Region, a higher incidence of tumours is observed in Rome municipality (RR 1.09; 95%CI 0.98-1.20) and in the Frosinone province (RR 1.07; 95%CI 0.91-1.25) for the whole 0-19-year age group. CONCLUSIONS: compared to the pooled AIRTUM figures for 2003-2008, Lazio Region showed a higher incidence for all cancers, both in children and adolescents, and for specific tumours, such as leukaemia in children and thyroid carcinoma in adolescents. Apart from the diverse observation period, these differences may be due to a higher registry sensitivity of the childhood specialized registry compared to general population registries. The observed incidence excesses for specific geographical areas and tumours deserve further investigations. Overall, in its first seven years of activity, the Lazio childhood cancer registry was able to provide reliable epidemiological figures of cancer incidence in children and adolescents in the Italian context.

[A suspect cluster of childhood cancer in Valle di Ledro (Province of Trento, Northern Italy). Epidemiological evaluation, risk management, and communication activities, 2018-2020]. / Un sospetto cluster di tumori infantili in Valle di Ledro (provincia di Trento). Valutazione epidemiologica e attività di comunicazione e gestione del rischio. Anni 2018-2020.

BACKGROUND: leukaemia is the most prevalent form of childhood cancer, an overall rare condition in childhood. Even few cases occurring in a small community can cause considerable apprehension among the population. From 2014 to 2017, 4 cases of childhood cancer occurred in Valle di Ledro, a municipality of 5,300 inhabitants in Province of Trento (Northern Italy), and a group of concerned citizens asked provincial health authorities for an investigation. OBJECTIVES: to address the community's health needs by verifying the hypothesis of a cluster of childhood cancer and through effective risk communication activities. DESIGN: retrospective cohort analysis based on data from the Cancer registry of the Autonomous Province of Trento and data collected from hospital discharge records. The communication activities were carried out according to the recommendations published by Epidemiologia&Prevenzione in 2016 in a Supplement "Childhood cancers, risk factors and investigation models for the evaluation of spatio-temporal clusters". SETTING AND PARTICIPANTS: Valle di Ledro, a municipality of 5,300 inhabitants in the Province of Trento. The participants in risk communication process were: city council; grassroot committee of concerned parents; health workforce of different services (epidemiology, cancer registry, public health; environmental health; primary health care; personnel of the Environmental Protection Agency; journalists; general population. The participants in the statistical analyses were: children of 0-14 years of age who were diagnosed a cancer from 1998 to 2014 in the Province of Trento (N. 212); leukaemia (N. 84) and acute lymphoblastic leukaemia (N. 66) incident cases in the period 1998-2017 in Trento province. MAIN OUTCOME MEASURES: verification of the presence of a cluster of childhood cancers; degree of consensus and collaboration of the different community stakeholders to the survey procedures and acceptance of the final results; atmosphere in public assemblies and feedback in the local press. RESULTS: a total of 212 incident cancer cases in children 0-14 years have been registred in Province of Trento from 1998 to 2014, leukaemia in 35% (N. 74) cases. From 2015 to 2017, another 10 cases of leukaemia occurred, for a total of 84 cases of leukaemia from 1998 to 2017. In the years from 1998 to 2017, in Valle di Ledro, taking the Italian population as reference group, the standardized incidence ratios (SIRs) were the following: cancer, all types 1,47 (IC95% 0,40-3,76); leukaemia 3,39 (IC95% 0,70-9,90), LLA 2,81 (IC95% 0,34-10,16). No cluster emerged from the geographical analyses. From the very beginning of the risk management approach, a decision-making working group was set up applying a participatory approach. Group members included the city council and the local committee of concerned parents and experts from different services of the local health unit. Data analyses was delegated to a technical working group that reported back to the decision-making group. Members of the technical working group were supervised by external experts. Following this approach, it was possible to establish a climate of trust and credibility. The involvement of all stakeholders right from the start in a totally transparent process was a key element of success. CONCLUSIONS: the cluster hypothesis was rejected for both childhood cancer (all types) and leukaemia (all types and ALL). The implementation of the risk communication process recommended by the AIE guidelines was successful in establishing a climate of reciprocal trust that allowed to overcome inevitable moments of conflict in a productive manner. Thanks to this positive atmosphere, the communication of the results of the statistical analyses was effective in reassuring the population.

Stage at diagnosis and survival by stage for the leading childhood cancers in three populations of sub-Saharan Africa.

The lack of accurate population-based information on childhood cancer stage and survival in low-income countries is a barrier to improving childhood cancer outcomes. In our study, data from three population-based registries in sub-Saharan Africa (Abidjan, Harare and Kampala) were examined for children aged under 15. We assessed the feasibility of assigning stage at diagnosis according to Tier 1 of the Toronto Childhood Cancer Stage Guidelines for patients with non-Hodgkin lymphoma [including Burkitt lymphoma (BL)], retinoblastoma and Wilms' tumour. Patients were actively followed-up, allowing calculation of 3-year relative survival by cancer type and registry. Stage-specific observed survival was estimated. The cohort comprised 381 children, of whom half (n = 192, 50%) died from any cause within 3 years of diagnosis. Three-year relative survival varied by malignancy and location and ranged from 17% [95% confidence interval (CI) = 6%-33%] for BL in Harare to 57% (95% CI = 31%-76%) for retinoblastoma in Kampala. Stage was assigned for 83% of patients (n = 317 of 381), with over half having metastatic or advanced disease at diagnosis (n = 166, 52%). Stage was a strong predictor of survival for each malignancy; for example, 3-year observed survival was 88% (95% CI = 68%-96%) and 13% (4%-29%) for localised and advanced BL, respectively (P < .001). These are the first data on stage distribution and stage-specific survival for childhood cancers in Africa. They demonstrate the feasibility of the Toronto Stage Guidelines in a low-resource setting and highlight the value of population-based cancer registries in aiding our understanding of the poor outcomes experienced by this population.

Role of radiotherapy and chemotherapy in the risk of leukemia after childhood cancer: An international pooled analysis.

Childhood cancer survivors are at increased risk for second primary leukemia (SPL), but there is little consensus on the magnitude of some risk factors because of the small size of previous studies. We performed a pooled analysis of all published studies with detailed treatment data, including estimated active bone marrow (ABM) dose received during radiation therapy and doses of specific chemotherapeutic agents for childhood cancer diagnosed from 1930 through 2000, in order to more thoroughly investigate treatment-related risks of SPL. A total of 147 SPL cases (of which 69% were acute myeloid leukemia [AML]) were individually matched to 522 controls, all from four case-control studies including patients from six countries (France, United Kingdom, United States, Canada, Italy and Netherlands). Odds ratios (OR) and corresponding 95% confidence intervals (CIs) were calculated using conditional logistic regression, and the excess OR per Gray (EOR/Gy) was also calculated. After accounting for the other therapies received, topoisomerase II inhibitor was associated with an increased SPL risk (highest tertile vs none: OR = 10.0, 95% CI: 3.7-27.3). Radiation dose to the ABM was also associated with increased SPL risk among those not receiving chemotherapy (EOR/Gy = 1.6, 95% CI: 0.1-14.3), but not among those who received chemotherapy (CT). SPL were most likely to occur in the first decade following cancer treatment. Results were similar when analyses were restricted to AML. The evidence of interaction between radiation and CT has implications for leukemogenic mechanism. The results for topoisomerase II inhibitors are particularly important given their increasing use to treat childhood cancer.

Residential proximity to pesticide application as a risk factor for childhood central nervous system tumors.

BACKGROUND: Pesticide exposures have been examined previously as risk factors for childhood brain cancers, but few studies were able to assess risk from specific agents. OBJECTIVE: To evaluate risks for childhood central nervous system tumors associated with residential proximity to agricultural pesticide applications. METHODS: Using the California Cancer Registry, we identified cancer cases less than 6 years of age and frequency matched them by year of birth to 20 cancer-free controls identified from birth certificates. We restricted analyses to mothers living in rural areas and births occurring between 1998 and 2011, resulting in 667 cases of childhood central nervous system tumors and 123,158 controls. Possible carcinogens were selected per the Environmental Protection Agency's (US. EPA) classifications, and prenatal exposure was assessed according to pesticides reported by the California Department of Pesticide Regulation's (CDPR) Pesticide Use Reporting (PUR) system as being applied within 4000m of the maternal residence at birth. We computed odds ratios for individual pesticide associations using unconditional logistic and hierarchical regression models. RESULTS: We observed elevated risks in the hierarchical models for diffuse astrocytoma with exposure to bromacil (OR: 2.12, 95% CI: 1.13-3.97), thiophanate-methyl (OR: 1.64, 95% CI: 1.02-2.66), triforine (OR: 2.38, 95% CI: 1.44-3.92), and kresoxim methyl (OR: 2.09, 95% CI: 1.03-4.21); elevated risks for medulloblastoma with exposure to chlorothalonil (OR: 1.78, 95% CI: 1.15-2.76), propiconazole (OR: 1.60, 95% CI: 1.02, 2.53), dimethoate (OR: 1.60, 95% CI: 1.06, 2.43), and linuron (OR: 2.52, 95% CI: 1.25, 5.11); and elevated risk for ependymoma with exposure to thiophanate-methyl (OR: 1.72, 95% CI: 1.10-2.68). CONCLUSION: Our study suggests that exposure to certain pesticides through residential proximity to agricultural applications during pregnancy may increase the risk of childhood central nervous system tumors.

Parental education and cancer mortality in children, adolescents, and young adults: A case-cohort study within the 2011 Italian census cohort.

BACKGROUND: Progress in the treatment of juvenile cancers has led to remarkable improvements in survival. However, not all families have the resources to cope with the burden that such diseases require. This study was aimed at evaluating the association between parental education and cancer mortality in children, adolescents, and young adults. METHODS: This was a case-cohort study based on 1889 cancer cases and 108,387 noncases sampled from the 2011 Italian census cohort of 10,964,837 individuals younger than 20 years and followed for 6 years. Mortality rate ratios (MRRs) were estimated for individuals with parents with high and intermediate levels of education (International Standard Classification of Education [ISCED] levels 5-8 and 3-4, respectively) in comparison with individuals with less educated parents (ISCED levels < 3) through multiple Poisson regression models. RESULTS: Over the follow-up, 684, 858, and 347 cancer cases with parents with the lowest, intermediate, and highest levels of education, respectively, were registered. In comparison with the individuals with parents with the lowest level of education, the MRR from all neoplasms was 0.92 (95% confidence interval [CI], 0.83-1.03) for those with parents with an intermediate level of education and 0.83 (95% CI, 0.72-0.95) for those with parents with the highest level of education. The MRRs from all neoplasms for individuals with parents with the highest level of education were 0.88 (95% CI, 0.69-1.11) among children, 0.87 (95% CI, 0.70-1.06) among adolescents, and 0.64 (95% CI, 0.50-0.83) among young adults. CONCLUSIONS: Children, adolescents, and young adults with highly educated parents have reduced mortality from cancer. This calls for further efforts to optimize treatment for children of less educated parents.

Pediatric Cancers among Alaska Native People.

OBJECTIVE: To evaluate the descriptive epidemiology of pediatric cancers among Alaska Native people. STUDY DESIGN: We used data from the Alaska Native Tumor Registry, a population-based registry capturing cancer information among Alaska Native people 1969-present. Specifically, we examined all cases of cancer diagnosed among individuals ages 0-19 years. Cases were classified according to the International Classification of Childhood Cancers, 3rd edition (ICCC-3). We estimated incidence and distribution of cases by ICCC-3 cancer site, comparing between the time periods 1969-1996 and 1997-2016. We assessed 12-month and 5-year cause-specific survival, and examined differences over the time period, adjusted for age, sex, and ICCC-3 site. RESULTS: Incidence rates of pediatric cancers increased between 1969 and 1996 (n = 134) and 1997 and 2016 (n = 186) among Alaska Native people, from 139.8 in 1 000 000 (95% CI, 116.99-165.7) to 197.54 in 1 000 000 (95% CI, 170.1-228.1). Distribution of ICCC-3 sites differed between time periods (P < .0001). Finally, cancer survival was high; the 12-month survival probability from all ICCC-3 sites combined was 0.88 (95% CI, 0.84-0.92) and the 5-year survival probability was 0.76 (95% CI, 0.70-0.81) for 1969-2016. After adjusting for age, sex, and ICCC-3 site, we observed a 57% decrease in the risk of death when comparing Alaska Native pediatric cancer cases diagnosed in 1997-2016 with those diagnosed in 1969-1996. CONCLUSIONS: This information will be of value for our understanding of pediatric cancers among Indigenous peoples of the US, and will also be informative for clinicians providing care to this population.

Vincristine-induced peripheral neurotoxicity: A prospective cohort.

Vincristine-induced peripheral neuropathy (VIPN) is a serious and pervasive problem, affecting 12-78% of pediatric patients, based on retrospective studies. The study objective was to prospectively collect a cohort of well-phenotyped patients receiving vincristine in order to accurately classify and grade their neurotoxicity. All children in British Columbia with leukemia or lymphoma requiring vincristine between 2013 and 2016 were approached for consent. Those recruited were assessed by occupational and physiotherapists at baseline, mid and endpoint of their treatment. Assessments included the Bruininks-Oseretsky Test of Motor Proficiency - 2nd ed. (BOT-2), strength, "Timed up and go" test and vibration sensibility. Seventy-two patients consented (age: 2.0-18.7 years). The majority were below average for age on one or more BOT-2 domains at midpoint (N = 32/45, 71%), which decreased by the endpoint (N = 19/41, 46%, p = .049). Six patients showed severe VIPN throughout treatment (N = 6/53, 11%), defined as a BOT-2 score well below average. Muscle strength for wrist extension/flexion, anterior tibialis and peronei decreased significantly between baseline (Median = 5) and midpoint (Median = 4), with no significant change noted by endpoint. Most patients had normal vibration sensibility in lower (N = 30/60, 50%) and upper limbs (N = 26/38, 68%). In conclusion, with no differences between time points. VIPN is highly prevalent among patients with pediatric cancer, causing significant morbidity and functional deficits. Identification of risk factors would allow for resource appropriation to patients at higher risk, as well as potentially permitting dose escalation in patients with low toxicity to improve survival.

Genome sequencing analysis of blood cells identifies germline haplotypes strongly associated with drug resistance in osteosarcoma patients.

BACKGROUND: Osteosarcoma is the most common malignant bone tumor in children. Survival remains poor among histologically poor responders, and there is a need to identify them at diagnosis to avoid delivering ineffective therapy. Genetic variation contributes to a wide range of response and toxicity related to chemotherapy. The aim of this study is to use sequencing of blood cells to identify germline haplotypes strongly associated with drug resistance in osteosarcoma patients. METHODS: We used sequencing data from two patient datasets, from Inova Hospital and the NCI TARGET. We explored the effect of mutation hotspots, in the form of haplotypes, associated with relapse outcome. We then mapped the single nucleotide polymorphisms (SNPs) in these haplotypes to genes and pathways. We also performed a targeted analysis of mutations in Drug Metabolizing Enzymes and Transporter (DMET) genes associated with tumor necrosis and survival. RESULTS: We found intronic and intergenic hotspot regions from 26 genes common to both the TARGET and INOVA datasets significantly associated with relapse outcome. Among significant results were mutations in genes belonging to AKR enzyme family, cell-cell adhesion biological process and the PI3K pathways; as well as variants in SLC22 family associated with both tumor necrosis and overall survival. The SNPs from our results were confirmed using Sanger sequencing. Our results included known as well as novel SNPs and haplotypes in genes associated with drug resistance. CONCLUSION: We show that combining next generation sequencing data from multiple datasets and defined clinical data can better identify relevant pathway associations and clinically actionable variants, as well as provide insights into drug response mechanisms.

Brain gliomas and growth factors: immunohistochemical, immunofluorescence, flow cytometry and RT-PCR profile in pediatric age.

Gliomas represent over 50% of tumors occurring in children. Evidence suggests that glioma stem cells (GSCs), maintained by the transforming growth factor-beta (TGF-ß1) pathway, and vascularization substantially contribute to tumor aggressiveness. The identification of important angiogenic factors such as vascular endothelial growth factor (VEGF) may represent a crucial step in the therapeutic approach against tumor growth and metastatic diffusion. The aim of this study was to identify the expression of TGF-ß1, VEGF and VEGF-receptors in brain gliomas. Specimens of 16 gliomas and 4 controls from children aged 0.2-14 years were used in the study. Immunohistochemical analysis and gene expression study from specimens was performed. Flow cytometry analysis on GSCs was performed to ascertain the expression of VEGF and VEGF-R2 in the tumor stem cell compartment. Newly diagnosed gliomas mainly showed moderate to strong VEGF immunostaining and increased expression of pro-inflammatory molecules in glioma cells. The proportion of TGF-ß1 positive endothelial cells was markedly lower in normal brain vessels compared to tumor vessels. These findings demonstrate that the glioma mass is constituted by a phenotypically immature anoxic central area with a proliferating hypoxic layer; the peripheral area is characterized by cell types with a higher degree of differentiation expressing pro-angiogenic factors. Our data have proven that GSCs play a central role in promoting glioma neovascularization. These findings are useful to understand glioma vascularization, have relevant implications in the therapeutic options and may favor new insights into stem cells biology and suggest therapeutic opportunities for the anti-vascular treatment strategy.

Residential mobility in early childhood and the impact on misclassification in pesticide exposures.

Studies of environmental exposures and childhood cancers that rely on records often only use maternal address at birth or address at cancer diagnosis to assess exposures in early childhood, possibly leading to exposure misclassification and questionable validity due to residential mobility during early childhood. Our objective was to assess patterns and identify factors that may predict residential mobility in early childhood, and examine the impact of mobility on early childhood exposure assessment for agriculturally applied pesticides and childhood cancers in California. We obtained the addresses at diagnosis of all childhood cancer cases born in 1998-2011 and diagnosed at 0-5 years of age (n = 6478) from the California Cancer Registry (CCR), and their birth addresses from linked birth certificates. Controls were randomly selected from California birth records and frequency matched (20:1) to all cases by year of birth. We obtained residential histories from a public-record database LexisNexis for both case (n = 3877 with age at diagnosis 1-5 years) and control (n = 99,262) families. Logistic regression analyses were conducted to assess the socio-demographic factors in relation to residential mobility in early childhood. We employed a Geographic Information System (GIS)-based system to estimate children's first year of life exposures to agriculturally applied pesticides based on birth vs diagnosis address or residential histories based upon Lexis-Nexis Public Records and assessed agreement between exposure measures using Spearman correlations and kappa statistics. Over 20% of case and control children moved in their first year of life, and 55% of children with cancer moved between birth and diagnosis. Older age at diagnosis, younger maternal age, lower maternal education, not having a Hispanic ethnic background, use of public health insurance, and non-metropolitan residence at birth were predictors of higher residential mobility. There was moderate to strong correlation (Spearman correlation = 0.76-0.83) and good agreement (kappa = 0.75-0.81) between the first year of life exposure estimates for agricultural pesticides applied within 2 km of a residence relying on an address at birth or at diagnosis or LexisNexis addresses; this did not differ by outcome status, but agreement decreased with decreasing buffer size, and increasing distance moved or age at diagnosis. These findings suggest that residential addresses collected at one point in time may represent residential history in early childhood to a reasonable extent; nevertheless, they exposure misclassification in the first year of life remains an issue. Also, the highest proportion of women not captured by LexisNexis were Hispanic women born in Mexico and those living in the lowest SES neighborhoods, i.e. possibly those with the higher environmental exposures, as well as younger women and those with less than high school education. Though LexisNexis only captures a sub-population, its data may be useful for augmenting address information and assessing the extent of exposure misclassification when estimating environmental exposures in large record linkage studies. Future research should investigate how to correct for exposure misclassification introduced by residential mobility that is not being captured by records.

Medulloblastoma and central nervous system germ cell tumors in adults: is pediatric experience applicable?

Medulloblastoma and central nervous system (CNS) germ cell tumors are very rare in adults, while they account for 25% and 5% of brain tumors in children, respectively (Pastore et al. Eur J Cancer 42:2064-208, 2006). Pediatric experiences, mostly from randomized and controlled clinical trials, have led to different tailored treatments, based on various risk factors, including histology, and extent of disease. For medulloblastoma, biological features have recently emerged that enable therapies to be scaled down in some cases, or pursued more aggressively in the event of chromosomal and/or genetic alterations (Massimino et al. Crit Rev Oncol Hematol 105:35-51, 2016). Such refinements are still impossible for adult patients due to the lack of similar clinical trials that might provide the same or a different understanding regarding patients' prognosis, long-term survival, quality of life, and acute and late toxicities. This review aims to contribute to the debate on the treatment of adults with these two diseases and promote the creation of broad-based, national and international trials to advance our knowledge in this area and to share the skills between pediatric and adult oncologists as adolescent and young adults (AYA) brain tumor national boards are currently requiring.

The prognostic importance of TGF-ß, TGF-ß receptor, and fascin in childhood solid tumors.

Fascin plays a role in tumor metastasis under the influence of TGF-ß, each potentiating the effect of the other. We retrospectively investigated whether there was a prognostic relationship between TGF-ß and fascin, and disease stage, local recurrence, metastasis tendency, and response to treatment. Twelve neuroblastomas, 17 osteosarcomas, 14 Ewing's sarcomas, 15 rhabdomyosarcoma cases, and 8 rare solid tumors were included. Serum TGF-ß levels were high at the time of diagnosis in all groups (p = .015) and decreased significantly during remission (p = .008). Serum TGF-ß values in the relapse period rarely reached high levels at the time of diagnosis and even stayed under the control group values (p = .017). When TGF-ß receptor expression in tumor tissues was evaluated, the association of TGF-ß receptor positivity with metastatic disease and advanced stage was striking. We found that 88% of rhabdomyosarcoma cases with alveolar histopathology expressed the TGF-ß receptor, and the association between TGF-ß receptor positivity and alveolar histopathology seemed to be a negative prognostic marker. When fascin levels were evaluated in childhood solid tumor tissue, the risk of relapse increased when the fascin total score at diagnosis was >4. This is one of the few studies including prognostic markers such as serum TGF-ß, tissue TGF-ß, TGF-ß receptor, and fascin in pediatric solid tumors. Considering the poor prognosis of advanced stage pediatric solid tumors and the need for biomarkers to predict which patient might need more intensive therapy or warrant closer follow-up afterward, we think that TGF-ß, TGF-ß receptor, and fascin expression have an important prognostic role.

Is Whole-Exome Sequencing an Ethically Disruptive Technology? Perspectives of Pediatric Oncologists and Parents of Pediatric Patients With Solid Tumors.

BACKGROUND: It has been anticipated that physician and parents will be ill prepared or unprepared for the clinical introduction of genome sequencing, making it ethically disruptive. PROCEDURE: As a part of the Baylor Advancing Sequencing in Childhood Cancer Care study, we conducted semistructured interviews with 16 pediatric oncologists and 40 parents of pediatric patients with cancer prior to the return of sequencing results. We elicited expectations and attitudes concerning the impact of sequencing on clinical decision making, clinical utility, and treatment expectations from both groups. Using accepted methods of qualitative research to analyze interview transcripts, we completed a thematic analysis to provide inductive insights into their views of sequencing. RESULTS: Our major findings reveal that neither pediatric oncologists nor parents anticipate sequencing to be an ethically disruptive technology, because they expect to be prepared to integrate sequencing results into their existing approaches to learning and using new clinical information for care. Pediatric oncologists do not expect sequencing results to be more complex than other diagnostic information and plan simply to incorporate these data into their evidence-based approach to clinical practice, although they were concerned about impact on parents. For parents, there is an urgency to protect their child's health and in this context they expect genomic information to better prepare them to participate in decisions about their child's care. CONCLUSIONS: Our data do not support the concern that introducing genome sequencing into childhood cancer care will be ethically disruptive, that is, leave physicians or parents ill prepared or unprepared to make responsible decisions about patient care.

Going back to class I: MHC and immunotherapies for childhood cancer.

After decades of unfulfilled promise, immunotherapies for cancer have reached a tipping point, with several FDA approved products now on the market and many more showing promise in both adult and pediatric clinical trials. Tumor cell expression of MHC class I has emerged as a potential determinant of the therapeutic success of many immunotherapy approaches. Here we review current knowledge regarding MHC class I expression in pediatric cancers including a discussion of prognostic significance, the opposing influence of MHC on T-cell versus NK-mediated therapies, and strategies to reverse or circumvent MHC down-regulation.