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Objective This study investigated the course, predictors, and impact of caregiving stress on the functioning of primary caregivers of children with cancer during the first year after a child's cancer diagnosis. Methods Primary caregivers (N = 95, 100% mother, 86% response rate) of consecutive newly diagnosed paediatric cancer patients (0–18 years) completed measures of caregiving stress, depressive symptoms, anxiety, and self-reported health at diagnosis, and 3, 6, and 12 months thereafter. Results Results indicated a significant decrease in caregiving stress (especially during the first 3 months after diagnosis). Caregiving stress was predicted by single marital status and the ill child being the mother's only child. Multilevel analyses, controlled for socio-demographic and medical covariates, showed that, over time, the decline in caregiving stress was accompanied by a reduction in depressive symptoms and anxiety. The amount of variance explained by caregiving stress was 53% for depressive symptoms, 47% for anxiety, and 3% for self-reported health. Conclusions The present study suggests that caregiving stress is an important factor in understanding parental adjustment to childhood cancer. This offers possibilities for developing interventions aimed at preventing caregiving stress, and strengthening mothers' confidence in their ability to provide good care

Purpose/Objectives: To explore the response shift phenomenon in pediatric patients with cancer and to determine its effects on ratings of health-related quality of life (HRQOL).Design: Retrospective pre- and post-test design.Setting: Pediatric oncology department in the northern part of the Netherlands.Sample: 37 children newly diagnosed with cancer and 80 parents.Methods: The then-test method was used to determine response shift. HRQOL was assessed within two weeks postdiagnosis (pretest) and three months later (post-test) using both child and parent reports of PedsQL and Cantril's ladder. The post-test and then-test were administered concurrently.Main Research Variables: Overall and multidimensional HRQOL.Findings: Scores on Cantril's then-test were lower than the pretest in both child and parent reports, indicating response shift in the assessment of overall HRQOL. Children experienced a greater response shift than parents. No differences were found between the PedsQL then- and pretests.Conclusions: Both child- and parent-report ratings of overall HRQOL were affected by response shift, resulting in an underestimation of the improvement in overall HRQOL between diagnosis and three months postdiagnosis. No response shift was demonstrated in the more specific domains of HRQOL (PedsQL).Implications for Nursing: Knowledge of the response shift phenomenon helps nurses to better interpret the outcomes of HRQOL. The use of the PedsQL instrument is recommended in future studies that aim to demonstrate changes in HRQOL.

PURPOSE Infections are a major cause of morbidity and mortality in pediatric cancer patients. The aim of this study was to establish the microbiological spectrum and the susceptibility patterns of bacteremia-causing bacteria in pediatric cancer patients with febrile neutropenia in relation to the use of prophylactic and empirical antibiotics. METHODS We analyzed positive blood cultures of pediatric cancer patients presenting with febrile neutropenia between 2004 and 2011 in Groningen and Amsterdam (the Netherlands) and in Bern (Switzerland), using different antibiotic prophylactic and empirical regimens. RESULTS A total of 156 patients with 202 bacteremias, due to 248 bacteria species, were enrolled. The majority (73%) of bacteremias were caused by Gram-positive bacteria. Gram-negative bacteria, especially Pseudomonas aeruginosa, were observed significantly more often in Bern, where no fluoroquinolone prophylaxis was used. Ciprofloxacin-resistant bacteria were cultured more often from patients who did receive ciprofloxacin prophylaxis, compared to the patients who did not (57 versus 11%, p = 0.044). CONCLUSIONS Gram-positive bacteria predominated in this study. We showed that the use of prophylactic antibiotics in pediatric cancer patients was associated with increased resistance rates, which needs further study. The strategy for empiric antimicrobial therapy for febrile neutropenia should be adapted to local antibiotic resistance patterns.

Purpose: To perform a systematic literature review for critical evaluation of prevalence and factors contributing to malnutrition in childhood cancer. Methods: A systematic search resulting in 46 suitable articles. Results: Due to lack of uniform criteria and adequate studies, the prevalence rates of malnutrition can only be estimated. Based on strengths and weaknesses of included references, prevalence rates are estimated to be 0-10% for leukemia, 20-50% for neuroblastoma, and 0-30% for other malignancies. Whether energy deficiency or inflammation contributed to malnutrition could not be confirmed because the occurrence of energy deficit (low energy intake, increased metabolic rate) or inflammation (related to cachexia) was not convincing. Also, a relationship between these factors and malnutrition was not studied. Conclusion: Longitudinal studies are needed to determine which children are at risk of malnutrition, and to investigate the impact of energy deficiency and inflammation on the nutritional status and body composition of childhood cancer patients. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Purpose In this study, we evaluated C-reactive protein (CRP), interleukin (IL)-8, procalcitonin (PCT), and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as predictors for bacterial infection in febrile neutropenia, plus their usefulness in febrile neutropenia during chemotherapy-induced gastrointestinal mucositis. Methods Plasma was obtained from pediatric oncology patients at presentation with febrile neutropenia (n = 43) and 24–48 h later (n = 17). The patients were classified as having or not having a bacterial infection. Plasma was also obtained of patients in the absence and in the presence of mucositis (n = 26). Results At presentation with febrile neutropenia, median IL-8 and PCT levels were significantly increased in patients with a bacterial infection, in contrast to CRP and sTREM-1. IL-8 was the most sensitive marker for the early detection of bacterial infection, in combination with clinical parameters or PCT the sensitivity reached 100%. After 24–48 h, only PCT was significantly elevated during bacterial infection. IL-8 levels were significantly increased during mucositis. Mucositis did not cause considerable changes in PCT levels. Conclusions IL-8 is the most useful marker for the early detection of bacterial infections, compared with CRP, PCT, and sTREM-1. IL-8 in combination with clinical parameters or PCT might be even more useful. Gastrointestinal mucositis alone does not affect PCT levels, in contrast to IL-8 levels, and therefore, PCT might be more useful for the detection of bacterial infections during mucositis than IL-8.

Infections are a major cause of morbidity and mortality in children with acute lymphoblastic leukemia (ALL). Susceptibility to infections increases as the neutrophil count decreases. Despite identical treatment patients vary considerably in the number of neutropenic episodes. Toll-like receptor 4 (TLR4) has been shown to have a role in inhibiting apoptosis of neutrophils. Therefore, we hypothesized that polymorphisms in the TLR4 gene may influence the number of chemotherapy-induced neutropenic episodes. Eight single-nucleotide polymorphisms (SNPs) of the TLR4 gene were determined in 194 children aged 0-17 years, who were diagnosed with ALL. We compared the genotype distributions of the SNPs with the frequency of neutropenic episodes during treatment with chemotherapeutic regimens. The number of neutropenic episodes varied from 0 to 17, with a median of four neutropenic episodes. Four SNPs in the TLR4 gene (rs10759931, rs11536889, rs1927911 and rs6478317) were associated with an increased risk of developing chemotherapy-induced neutropenia, each sustaining correction for multiple testing. Further studies are required to elucidate whether pediatric patients with ALL with the particular SNPs in the TLR4 gene also experience more infections and would benefit from prophylactic antibiotic treatment, by a reduction of morbidity and mortality due to infections.

Background Acute Myeloid Leukemia (AML) bone marrow biopsies at diagnosis display enhanced angiogenesis and increased VEGFA expression. In a xenograft mouse model it was described that availability of free VEGFA versus bound VEGFA is related to different vascular morphology. In this study we investigate the relationship between vascular morphology within AML bone marrow biopsies and AML derived VEGFA levels. Methods Vessel count and surface area (Chalkley count) were calculated in AML bone marrow biopsies at diagnosis (n = 32), at remission (n = 8) and Normal Bone Marrow (n = 32) using immunohistochemical staining for FVIII, CD31, CTIV, SMA and VEGFA. VEGFA protein levels were measured. Results High vessel count was associated with an immature vessel status. Combining vessel count and Chalkley count different vessel morphology patterns were quantified within AML bone marrow biopsies. Three different subgroups could be distinguished. The subgroup (37.5% of the samples) exhibiting a high vessel count and vessels with predominantly large lumen (normal Chalkley count) was associated with high secreted VEGFA protein levels. Conclusion Different vasculature patterns are seen in AML bone marrow biopsies, defined by combining number and size of vessel. These quantified morphology patterns, combined with VEGFA levels, might be of value in the success of VEGF/VEGFR-signaling interference approaches.

High VEGFC mRNA expression of acute myeloid leukemia (AML) blasts is related to increased in vitro and in vivo drug resistance. Prognostic significance of VEGFC on long-term outcome and its associated gene expression profiles remain to be defined. We studied effect of VEGFC on treatment outcome and investigated gene expression profiles associated with VEGFC using microarray data of 525 adult and 100 pediatric patients with AML. High VEGFC expression appeared strongly associated with reduced complete remission rate (P = .004), reduced overall and event-free survival (OS and EFS) in adult AML (P = .002 and P < .001, respectively). Multivariable analysis established high VEGFC as prognostic indicator independent of cytogenetic risk, FLT3-ITD, NPM1, CEBPA, age, and white blood cell count (P = .038 for OS; P = .006 for EFS). Also, in pediatric AML high VEGFC was related to reduced OS (P = .041). A unique series of differentially expressed genes was identified that distinguished AML with high VEGFC from AML with low VEGFC, that is, 331 up-regulated genes (representative of proliferation, vascular endothelial growth factor receptor activity, signal transduction) and 44 down-regulated genes (eg, related to apoptosis) consistent with a role in enhanced chemoresistance. In conclusion, high VEGFC predicts adverse long-term prognosis and provides prognostic information in addition to well-known prognostic factors.

Background. The Currently used National Cancer Institute (NCI) adverse events criteria for mucosal barrier injury (MBI) are insufficient for use in children. We searched for objective, easily measurable indicators for MBI in children with cancer. Purpose. In children with acute myeloid leukemia, various MBI-related clinical and laboratory tests were investigated, reflecting clinical severity (NCI symptomatic adverse events criteria (gold standard), daily gut score (DGS)), inflammation (plasma and fecal interleukin-8 (IL-8), fecal calprotectin), enterocytic loss (plasma citrulline, ratio fecal human DNA/total DNA) and intestinal permeability (sugar absorption tests). Results. Intestinal MBI as detected by the NCI adverse events criteria was found in 55% of chemotherapy cycles, correlating well with the continuous DGS (n = 55, rho = 0.581; P

Progression in pediatric brain tumor growth is thought to be the net result of signaling through various protein kinase-mediated networks driving cell proliferation. Defining new targets for treatment of human malignancies, without a priori knowledge on aberrant cell signaling activity, remains exceedingly complicated. Here, we introduce kinome profiling using flow-through peptide microarrays as a new concept for target discovery. Comprehensive tyrosine kinase activity profiles were identified in 29 pediatric brain tumors using the PamChip kinome profiling system. Previously reported activity of epidermal growth factor receptor, c-Met, and vascular endothelial growth factor receptor in pediatric brain tumors could be appreciated in our array results. Peptides corresponding with phosphorylation consensus sequences for Src family kinases showed remarkably high levels of phosphorylation compared with normal tissue types. Src activity was confirmed applying Phos-Tag SDS-PAGE. Furthermore, the Src family kinase inhibitors PP1 and dasatinib induced substantial tumor cell death in nine pediatric brain tumor cell lines but not in control cell lines. Thus, this study describes a new high-throughput technique to generate clinically relevant tyrosine kinase activity profiles as has been shown here for pediatric brain tumors. In the era of a rapidly increasing number of small-molecule inhibitors, this approach will enable us to rapidly identify new potential targets in a broad range of human malignancies. [Cancer Res 2009;69(14):5987–95]

Background. Normally, humans are protected against infections by their anaerobic intestinal microorganisms providing colonization resistance. In immunocompromised patients, the endogenous intestinal gram-positive and gram-negative pathogens often cause infectious complications. Therefore, we analyzed the effect of chemotherapy treatment and antimicrobial prophylaxis on intestinal bacterial populations (microbiota) among pediatric patients with acute myeloid leukemia who are prone to intestinal mucositis and infections.Methods. During 36 chemotherapy cycles, fecal samples were collected from pediatric patients with acute myeloid leukemia. Fecal bacterial populations were analyzed by polymerase chain reaction denaturing gradient gel electrophoresis fingerprinting. Fluorescent in situ hybridization analysis with specific bacterial oligonucleotide probes was used to quantify the fecal bacteria.Results. During chemotherapy treatment, the total number of bacteria in fecal samples was 109 per gram of dry weight feces, which was 100-fold lower than than in healthy control samples. Fluorescent in situ hybridization analysis showed that this decrease was the result of an up to 10,000-fold decrease in anaerobic bacteria, partly compensated for by a 100-fold increase in potentially pathogenic enterococci. Additional experiments showed that both prophylactic and therapeutic use of antibiotics could not sufficiently explain the tremendous changes in intestinal microbial composition. In vitro tests showed a direct bacteriostatic effect of chemotherapeutics.Conclusions. Patients with acute myeloid leukemia treated with chemotherapy and prophylactic antibiotics are unable to maintain colonization resistance because of a decrease in anaerobic bacteria and an increase in potentially pathogenic aerobic enterococci. We hypothesize that this disturbance in the balance between anaerobic and aerobic bacteria will further increase the risk of gram-positive aerobic infections among immunocompromised patients with cancer.

Summary Background Genetic subtypes of acute lymphoblastic leukaemia (ALL) are used to determine risk and treatment in children. 25% of precursor B-ALL cases are genetically unclassified and have intermediate prognosis. We aimed to use a genome-wide study to improve prognostic classification of ALL in children. Methods We constructed a classifier based on gene expression in 190 children with newly diagnosed ALL (German Cooperative ALL [COALL] discovery cohort) by use of double-loop cross-validation and validated this in an independent cohort of 107 newly diagnosed patients (Dutch Childhood Oncology Group [DCOG] independent validation cohort). Hierarchical cluster analysis with classifying gene-probe sets revealed a new ALL subtype, the underlying genetic abnormalities of which were characterised by comparative genomic hybridisation-arrays and molecular cytogenetics. Findings Our classifier predicted ALL subtype with a median accuracy of 90·0% (IQR 88·3–91·7) in the discovery cohort and correctly identified 94 of 107 patients (accuracy 87·9%) in the independent validation cohort. Without our classifier, 44 children in the COALL cohort and 33 children in the DCOG cohort would have been classified as B-other. However, hierarchical clustering showed that many of these genetically unclassified cases clustered with BCR–ABL1 -positive cases: 30 (19%) of 154 children with precursor B-ALL in the COALL cohort and 14 (15%) of 92 children with precursor B-ALL in the DCOG cohort had this BCR–ABL1 -like disease. In the COALL cohort, these patients had unfavourable outcome (5-year disease-free survival 59·5%, 95% CI 37·1–81·9) compared with patients with other precursor B-ALL (84·4%, 76·8–92·1%; p=0·012), a prognosis similar to that of patients with BCR–ABL1 -positive ALL (51·9%, 23·1–80·6%). In the DCOG cohort, the prognosis of BCR–ABL1 -like disease (57·1%, 31·2–83·1%) was worse than that of other precursor B-ALL (79·2%, 70·2–88·3%; p=0.026), and similar to that of BCR–ABL1 -positive ALL (32·5%, 2·3–62·7%). 36 (82%) of the patients with BCR–ABL1 -like disease had deletions in genes involved in B-cell development, including IKZF1, TCF3, EBF1, PAX5, and VPREB1 ; only nine (36%) of 25 patients with B-other ALL had deletions in these genes (p=0·0002). Compared with other precursor B-ALL cells, BCR–ABL1 -like cells were 73 times more resistant to L-asparaginase (p=0·001) and 1·6 times more resistant to daunorubicin (p=0·017), but toxicity of prednisolone and vincristine did not differ. Interpretation New treatment strategies are needed to improve outcome for this newly identified high-risk subtype of ALL. Funding Dutch Cancer Society, Sophia Foundation for Medical Research, Paediatric Oncology Foundation Rotterdam, Centre of Medical Systems Biology of the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research, American National Institute of Health, American National Cancer Institute, and American Lebanese Syrian Associated Charities.

Background: In this national multicentre study, we examined the safety of reducing antibiotics in selected paediatric cancer patients with febrile neutropenia.Methods: Patients with signs of a bacterial infection and/or abnormal vital signs indicating sepsis were considered high risk and received antibiotic therapy. Remaining patients were allocated to low-or medium risk, depending on their interleukin-8 level. Low-risk patients did not receive any antibiotics and were discharged from the hospital after having been afebrile for 12 h. Medium-risk patients were re-evaluated after 72 h of antibiotic treatment and, in selected patients, antibiotics were stopped.Results: Two hundred thirty-three febrile neutropenic episodes in 141 paediatric cancer patients were included in the study. Sixty-four episodes were classified high risk (28%), 122 medium risk (52%), and 47 (20%) low risk. In the medium-risk group, antibiotics were stopped after 72 h in 50 in 122 episodes (41%). Median duration of antibiotic treatment and hospital admission was significantly lower in low-and medium-risk episodes with early discharge. No failures were observed in the medium-risk group with early discharge. In the low-risk group, six failures were observed (12.8%), due to coagulase-negative staphylococci-positive blood cultures and recurrent fever.Conclusion: We showed that it is safe to shorten antibiotic treatment to 72 h in selected medium-risk patients with febrile neutropenia, regardless of the neutrophil count. The safety of withholding antibiotics in selected low-risk paediatric cancer patients with febrile neutropenia requires further investigation, using more suitable definitions for safety. Reduction in hospital admissions allows children with cancer more time at home and consequently improves their quality of life. (C) 2015 Elsevier Ltd. All rights reserved.

In children with cancer a well-known risk factor for cardiotoxicity is a high cumulative dose of anthracyclines, but little is known about cardiac function in low-dose anthracycline-treated survivors. Also, it is unclear if a safe anthracycline-dose exists at all.Cardiac function was assessed in 23 long-term ALL-survivors with a median follow-up of 22 years (range 19.5-24.5) post-treatment. Age at diagnosis and current age were 5.0 (2.0-14.0) and 29.0 (24.0-39.0) years. All 23 survivors were treated according to DCLSG protocol ALL-5, including 18-25 Gy cranial irradiation. Thirteen of them received 4 x 25 mg/m(2) daunorubicin by randomization. Cardiac evaluation included blood pressure measurement, echocardiography, and (24 h-) electrocardiogram. Results were compared with an earlier assessment at median 12 years post-treatment.None of the survivors had cardiac abnormalities. Cardiac status of daunorubicin-treated survivors showed no deterioration compared with the previous assessment in 1995. CONCLUSION AND IMPLICATION FOR CANCER SURVIVORS: After prolonged follow-up (more than 20 years post-treatment), ALL-survivors treated with low dose daunorubicin had no clinical relevant deterioration of cardiac function.

Purpose 1. To assess health-related quality of life (HRQoL) of adult long term (up to 20 years) and very long term (>20 years) childhood cancer survivors, compared to the HRQoL of an age matched Dutch population sample. 2. To evaluate the impact of cancer-related adverse late effects on the functional, psychological and social health of childhood cancer survivors. Method The RAND-36 was used to assess HRQoL in all adult (⩾18 years) survivors who had attended the long-term follow-up clinic since 1995. The survivors were divided into two groups based on the length of follow-up: Group LF (long term follow-up, follow-up ⩽20 years, n = 129) and Group VLF (very long-term follow-up, follow-up >20 years, n = 184). Data on diagnosis, treatment and complications were obtained from medical records. Late effects were graded using the CTCAEv3. Results The RAND-36 was completed by 313 (86.2%) out of 363 eligible patients. Except for higher scores on the subscale Bodily pain, LF patients did not differ significantly on the RAND-36 subscales from the population sample; VLF patients had significant lower scores on the subscales Physical functioning ( P = 0.003), Social functioning, Vitality and General health perception ( P P Conclusion Childhood cancer survivors who were diagnosed more than 20 years ago have lower scores on the RAND 36, and have significantly more severe late effects than those diagnosed more recently. Patients with longer follow-up are more likely to become lost to follow-up. Time has come to establish new models of care for adult childhood cancer survivors, which are more flexible and appropriate to the needs of adult childhood cancer survivors.

intellectual functioning (verbal, performance and full-scale IQ) in 43 children treated for acute lymphoblastic leukaemia (ALL) with chemotherapy-only was evaluated in a nationwide, prospective, sibling-controlled study. Intellectual assessment was performed at diagnosis and repeated shortly after cessation of 2 years treatment, including intrathecal and systemic chemotherapy. Using hierarchical regression analysis, patients' and siblings' (n = 27) scores were longitudinally analysed and compared to assess possible changes and differences over time. At both assessments, before and after treatment, patients showed average scores on intelligence tests compared to population norms. Longitudinal analysis and cross-sectional comparisons revealed no significant differences between patients and controls. Young patients showed a small relative decline, albeit not significant, on performance-IQ compared to healthy siblings. Despite intensive and potentially neurotoxic treatment, no evident negative effects on intelligence were found. However, it cannot be precluded that younger patients are at risk for a small decline in PIQ. (c) 2006 Elsevier Ltd. All rights reserved.

Purpose: Cancer patients treated with cytostatic drugs often develop oral mucositis, considered to be a mucosal injury in which various cytokines, such as interleukin 8 (IL-8), may play a role. Plasma IL-8 is a systemic inflammatory response parameter. This study investigated whether oral mucositis affects plasma IL-8 levels in febrile neutropenic cancer patients. Patients and Methods: Patients (n = 57) who were hospitalized with chemotherapy-induced neutropenic fever were scored for oral mucositis on the second day of hospitalization according to a validated oral mucositis assessment scale (OMAS) and WHO toxicity grading. Patients (n = 20) with a clinical sepsis or local bacterial infection were excluded from this evaluation. The remaining 37 patients were divided in groups with and without oral mucositis. Results: The difference in plasma IL-8 level between patients with and without mucositis was not significant (P = 0.7). Similarly no difference was observed in the degree and duration of granulocytopenia. Conclusion: These results indicate that low-grade oral mucositis is not related to the systemic plasma IL-8 level in febrile neutropenic cancer patients without a clinical sepsis or local bacterial infection.

Aims: To study neuropsychological functioning of newly diagnosed children with acute lymphoblastic leukaemia (ALL) within two weeks after diagnosis in order to determine the feasibility of a sibling controlled prospective study design. Methods: Fifty consecutive patients (median age at testing 6.6 years, range 4–12) were included in a prospective, longitudinal, nationwide study. Treatment would include intrathecal and systemic chemotherapy according to the DCLSG ALL-9 protocol. Children were evaluated with an extensive neuropsychological battery including measures of intelligence, memory, attention, language, visual-constructive function, and fine-motor abilities within two weeks after start of the chemotherapy. The control group consisted of 29 healthy siblings (median age at testing 8.2 years, range 4–12), who were tested

BACKGROUND & AIMS: Under- and overnutrition are linked to adverse outcomes during and after childhood cancer treatment. Therefore, understanding the timing of weight loss and weight gain and their contributory factors is essential for improving outcomes. We aimed to determine in which period of treatment changes in nutritional status occurred and which factors contributed to these changes.METHODS: A prospective cohort study of 133 newly diagnosed cancer patients with hematological, solid, and brain malignancies was performed. Anthropometric data and related factors were assessed at 0, 3, 6 and 12 months after diagnosis.RESULTS: Despite initial weight loss at the beginning of treatment in patients with hematological and solid malignancies, body mass index (BMI) and fat mass (FM) increased within 3 months with 0.13 SDS (P < 0.001) and 0.05 SDS (P = 0.021) respectively. Increase continued during the following months and resulted in a doubling of the number of overnourished patients. Fat free mass (FFM), which was already low at diagnosis, remained low. During the entire study period about 17% of the patients were undernourished on the basis of low FFM. Tube feeding and diminished activity level were related to increases in BMI and %FM respectively. No relationship was found between energy intake or corticosteroids and increase in BMI or %FM.CONCLUSIONS: BMI and FM increased during and after the period of intensive treatment, while FFM remained low. Improvement of nutritional status might be accomplished by increasing physical activity from the early phase of treatment.

Little is known about the etiology of childhood acute lymphoblastic leukemia (ALL). The presence of atopic disease has been shown to protect against developing childhood ALL. The aim of this study was to examine whether single nucleotide polymorphisms (SNPs) in innate immunity genes previously associated with atopic disease, can elucidate the inverse association between childhood ALL and atopic disease. We studied 525 children, including 192 with childhood ALL, 149 with atopic disease and 184 healthy control subjects. We compared genotype distributions of 29 SNPs in genes of TLR2, TLR4, TLR6, TLR9, TLR10 and CD14 between the three groups and corrected for multiple testing. The genotype distributions of two SNPs in the TLR6 gene, rs5743798 and rs6531666, differed significantly between children with ALL, children with atopic disease and control subjects. Particularly in children with atopic eczema, risk alleles for atopic disease were observed more often than in control subjects, and less often in children with ALL than in control subjects. These findings support the immune surveillance hypothesis as an explanation for the protective association of atopic disease on childhood ALL. Further investigation is warranted to examine in more detail the role of innate immunity in the development of childhood ALL.

Item does not contain fulltext PURPOSE: For children with incurable cancer death usually is anticipated and preceded by a phase of palliative care. Despite recognition that parents have difficulty adapting to a palliative perspective there is little insight into this process. This study explored, from a parental perspective, the process parents go through when cure is no longer a possibility. PARTICIPANTS AND METHODS: A multicenter study using qualitative research was undertaken during the EoL phase. One-time and repeated open interviews were conducted with 44 parents of 23 children with incurable cancer. RESULTS: Feelings of loss play a prominent role during the EoL phase. Dealing with loss is a process of stepwise relinquishing that becomes manifest in an internal struggle between preservation and letting go. Preservation means that parents try to maintain the child's status quo. Letting go means parents give up their resistance to loss in service of their child's well-being. Although the relative measure of each changes over time, parents have great difficulty making the transition because it implies a change in source of control. A timely completion of this transition positively influences the child's well-being as well as the evaluation of enacted parenthood. CONCLUSION: For parents the essence of the palliative process is not to accept death but to deal with the loss of their child. Although the need to avoid loss and gain control by means of preservation is fully understandable, the study indicated that parents who made the transition to letting go had an increased receptiveness of their child's real situation and needs.

Objective: To investigate the preferences of children with cancer, their parents, and survivors of childhood cancer regarding medical communication with child patients and variables associated with these preferences.Methods: Preferences regarding health-care provider empathy in consultations, and children's involvement in information exchange and medical decision making were investigated by means of vignettes. Vignettes are brief descriptions of hypothetical situations, in which important factors are systematically varied following an experimental design. In total, 1440 vignettes were evaluated by 34 children with cancer (aged 8-16), 59 parents, and 51 survivors (aged 8-16 at diagnosis, currently aged 10-30). Recruitment of participants took place in three Dutch university-based pediatric oncology centers. Data were analyzed by multilevel analyses.Results: Patients, parents, and survivors indicated the importance of health-care providers' empathy in 81% of the described situations. In most situations (70%), the three respondent groups preferred information about illness and treatment to be given to patients and parents simultaneously. Preferences regarding the amount of information provided to patients varied. The preference whether or not to shield patients from information was mainly associated with patients' age and emotionality. In most situations (71%), the three respondent groups preferred children to participate in medical decision making. This preference was mainly associated with patients' age.Conclusions: To be able to adapt communication to parents' and patients' preferences, health-care providers should repeatedly assess the preferences of both groups. Future studies should investigate how health-care providers balance their communication between the sometimes conflicting preferences of patients and parents. Copyright (C) 2010 John Wiley & Sons, Ltd.

To evaluate the adverse late effects of ALL treatment on cognitive functions and brain morphology; to integrate the results of a neuropsychological and neuroradiological study.Cranial magnetic resonance imaging (MRI) and neuropsychological assessments (NA) were performed in 35 children treated for acute lymphoblastic leukemia (ALL) with cranial irradiation (CI) and intrathecal and intravenous methotrexate. Patients were under the age of 7 years (MD: 3.5 years) at diagnosis; median follow-up at MRI and NA was 8 years since diagnosis.MRI's were classified as definitely abnormal in 51% and as probably abnormal in another 17% of the patients. White matter damage was most frequently seen. MRI abnormalities were not related to CI dose or age at diagnosis. Patients showed significantly lower scores, compared to the norm group on measures of intelligence, verbal auditory memory, visual motor integration, and fine motor functioning. Lower scores significantly correlated with higher CI dose (25-32 Gy compared to 18-20 Gy) and younger age at diagnosis (4.0 years compared toor = 4.0 years). Forty percent of the patients had to be referred to schools for learning disabled.ALL treatment, including CI and MTX, at a young age is associated with persistent cognitive impairment and MRI abnormalities. However, no correlation was found between MRI results and neuropsychological or academic performance.

The Dutch Childhood Oncology Group (DCOG) has used two treatment strategies for children with acute lymphoblastic leukemia (ALL) based on Pinkel's St Jude Total Therapy or the Berlin-Frankfurt-Munster (BFM) backbone. In four successive protocols, 1734 children were treated. Studies ALL-6 and ALL-9 followed the Total Therapy approach; cranial irradiation was replaced by medium-dose methotrexate infusions and prolonged triple intrathecal therapy; dexamethasone was used instead of prednisone. Studies ALL-7 and ALL-8 had a BFM backbone, including more intensive remission induction, early reinduction and maintenance therapy without vincristine and prednisone pulses. The 5-year event-free survival and overall survival increased from 65.4 to 80.6% (P100 x 109/l, and T-lineage ALL have prognostic impact. We conclude that the chemotherapy-only approach in children with ALL in Total Therapy-based strategies and BFM-backbone treatment does not jeopardize survival and preserves cognitive functioning. This experience is implemented in the current DCOG-ALL-10 study using a BFM backbone and minimal residual disease-based stratification. Leukemia (2010) 24, 309-319; doi: 10.1038/leu.2009.258; published online 17 December 2009

Objective The aim of this study was to evaluate the results of home-based exercise counselling with feedback from a pedometer on fatigue in adult survivors of childhood cancer. Patients Adult survivors of childhood cancer were recruited from the long-term follow-up clinic of the University Medical Centre Groningen, The Netherlands. A score of 70 mm on a visual analogue scale (scale, 0–100 mm) for fatigue was used as an inclusion criterion. Controls were recruited by the survivors among their healthy siblings or peers. Methods During 10 weeks, the counselor encouraged the survivors to change their lifestyle and enhance daily physical activity such as walking, cycling, housekeeping and gardening. As a feedback to their physical activity, the daily number of steps of each survivor was measured by a pedometer and registered using an online step diary at the start of the programme and after 4 and 10 weeks. Fatigue was the primary outcome measure, assessed with the Checklist Individual Strength (CIS) at start (T0), 10 weeks (T10) and 36 weeks (T36). Thirty-three healthy age-matched control persons were asked to complete the CIS. Results Out of 486 cancer survivors, 453 were interested and were asked to complete the VAS to measure fatigue; 67 out of 254 respondents met the inclusion criteria, 21 refused, 46 were enrolled and eight dropped out during the study. The mean scores on the CIS in the survivors at T0 was 81.42 (SD ± 20.14) and at T10 62.62 (SD ± 20.68), which was a significant improvement (p

Contains fulltext : 81501.pdf (Publisher’s version ) (Open Access) BACKGROUND: The purpose of this article is to describe and evaluate the methodology of online focus group discussions within the setting of paediatric oncology. METHODS: Qualitative study consisting of separate moderated asynchronous online discussion groups with 7 paediatric cancer patients (aged 8-17), 11 parents, and 18 survivors of childhood cancer (aged 8-17 at diagnosis). RESULTS: All three participant groups could be actively engaged over a one-week period. Respondents highly valued the flexibility and convenience of logging in at their own time and place to join the discussion. Adolescent patients and survivors emphasized that the anonymity experienced made them feel comfortable to express their views in detail. The findings indicate a strong preference for online group discussions across all participant groups. CONCLUSION: The findings show that online focus group methodology is a feasible tool for collecting qualitative data within the setting of paediatric oncology, and may offer new opportunities to collect data in other hard-to-include populations. The evaluations seem to indicate that the online group discussions have given participants an opportunity to articulate their experiences and views in a way they might not have done in a traditional group discussion. 9 p.

Contains fulltext : 80380.pdf (Publisher’s version ) (Closed access) BACKGROUND: A population-based cohort of children aged 1-18 years with acute lymphoblastic leukaemia (ALL) was treated with a dexamethasone-based protocol (Dutch Childhood Oncology Group [DCOG] ALL-9). We aimed to confirm the results of the most effective DCOG ALL protocol for non-high-risk (NHR) patients to date (ALL-6), compare results with ALL-7 and ALL-8, and study prognostic factors in a non-randomised setting. METHODS: From Jan 1, 1997, until Nov 1, 2004, patients with ALL were treated according to the ALL-9 protocol in eight Dutch academic centres with their affiliated peripheral hospitals. Patients were stratified into NHR and high risk (HR) groups. HR criteria were white-blood-cell count of 50,000 cells per microL or more, T-cell phenotype, mediastinal mass, CNS or testicular involvement, and Philadelphia chromosome or MLL rearrangement; patients who did not fulfil these criteria were deemed to be NHR. The NHR group was treated with a three-drug induction (dexamethasone, vincristine, and asparaginase) for 6 weeks, medium-dose methotrexate for 3 weeks, then maintenance therapy. HR patients received a four-drug induction (as for the NHR patients plus daunorubicin) for 6 weeks, high-dose methotrexate for 8 weeks, and two intensification courses before receiving maintenance therapy. Triple intrathecal medication was given 13 times in NHR patients, 15 times in HR patients (17 times for patients with initial CNS involvement). No patient received cranial irradiation. Maintenance therapy was given until 109 weeks for all patients and consisted of mercaptopurine and methotrexate for 5 weeks, alternated with dexamethasone and vincristine for 2 weeks. Kaplan-Meier analysis was done on an intention-to-treat basis with event-free survival as the primary endpoint. This trial is registered at trialregister.nl, number NTR460/SNWLK-ALL-9. FINDINGS: 859 patients were recruited to the study. Complete remission was achieved in 592 (98.5%) of the 601 patients in the NHR group and 250 (96.9%) of the 258 in the HR group. Five patients in the NHR group and four in the HR group died during induction. Median follow-up for patients alive was 72.2 (range 4.8-132.7) months as of August, 2008. 5-year event-free survival was 81% (SE 1%) in all patients: 84% (2%) in NHR patients, and 72% (3%) in HR patients. Isolated CNS relapses occurred in 22 (2.6%) of 842 patients. In a multivariate analysis, DNA index was the strongest predictor of outcome (or=1.16; relative risk 0.42, 95% CI 0.22-0.78), followed by age (1-9 vs >or=10 years; 2.23, 1.60-3.11) and white-blood-cell count (or=50,000 cells per microL; 1.60, 1.13-2.26). INTERPRETATION: The overall results of the dexamethasone-based DCOG ALL-9 protocol are better than those of our previous Berlin-Frankfurt-Munster-based protocols ALL-7 and ALL-8. The results for NHR patients were achieved with high cumulative doses of dexamethasone and vincristine, but without the use of anthracyclines, etoposide, cyclophosphamide, or cranial irradiation, therefore minimising the risk of side-effects. FUNDING: Dutch Health Insurers.

Children with cancer treated with chemotherapy are susceptible to bacterial infections and serious infectious complications. However, fever and neutropenia can also result from other causes, for which no antibiotic treatment is needed. In the past decades attempts have been made to stratify the heterogeneous group of pediatric cancer patients with fever and neutropenia into high- and low-fisk groups for bacterial infections or infectious complications. Strategies for risk assessment have resulted in treatment regimens with early discharge or even no hospital admission at all, and/or treatment with oral or no antibiotics. We will provide a historical overview of the changing approach to low-risk fever and neutropenia, and we will also try to identify clear and objective parameters for risk assessment strategies and illustrate their relationship to innate immunity. In the future, new insights into genetic susceptibility on neutropenic fever might be of use in children with cancer with fever and neutropenia. (C) 2008 Elsevier Ireland Ltd. All fights reserved.

Research has provided evidence that tumor growth depends on the interaction of tumor cells with stromal cells, as already suggested in 1889 by Paget. Experimental and clinical studies have revealed that tumor stromal cells can be derived from bone marrow (BM)-derived progenitor cells, such as mesenchymal stern cells (MSCs), which can be mobilized into the circulation and incorporate into tumor micro-environments. Many observations indicate that, in the tumor micro-environment, MSCs have several tumor growth promoting functions, including expression of growth factors, promotion of tumor vessel formation and creation of tumor stem cell niches. This review will discuss the currently known tumor growth promoting BM-derived cells and focus on the role of MSCs in modulating tumor micro-environments. In addition, we will discuss the potential of inhibiting BM-derived cells and their utilization as cellular vehicles for selective delivery of cancer therapeutics as additional strategies in the treatment of cancer. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Contains fulltext : 51596.pdf ( ) (Open Access) BACKGROUND: Guidelines in paediatric oncology encourage health care providers to share relevant information with young patients and parents to enable their active participation in decision making. It is not clear to what extent this mirrors patients' and parents' preferences. This study investigated communication preferences of childhood cancer patients, parents, and survivors of childhood cancer. METHODS: Communication preferences were examined by means of online focus groups. Seven patients (aged 8-17), 11 parents, and 18 survivors (aged 8-17 at diagnosis) participated. Recruitment took place by consecutive inclusion in two Dutch university oncological wards. Questions concerned preferences regarding interpersonal relationships, information exchange and participation in decision making. RESULTS: Participants expressed detailed and multi-faceted views regarding their needs and preferences in communication in paediatric oncology. They agreed on the importance of several interpersonal and informational aspects of communication, such as honesty, support, and the need to be fully informed. Participants generally preferred a collaborative role in medical decision making. Differences in views were found regarding the desirability of the patient's presence during consultations. Patients differed in their satisfaction with their parents' role as managers of the communication. CONCLUSION: Young patients' preferences mainly concur with current guidelines of providing them with medical information and enabling their participation in medical decision making. Still, some variation in preferences was found, which faces health care providers with the task of balancing between the sometimes conflicting preferences of young cancer patients and their parents.

Contains fulltext : 51905.pdf (Publisher’s version ) (Closed access) We report an increased incidence of infectious deaths during maintenance treatment of the ninth protocol for acute lymphoblastic leukaemia of the Dutch Childhood Oncology Group (DCOG-ALL-9). The main difference in maintenance treatment between DCOG-ALL-9 and the DCOG-ALL-7 and DCOG-ALL-8 protocols is the interruption of methotrexate and 6-mercaptopurine by vincristine (2mg/m(2) weekly) and dexamethasone (6mg/m(2) daily) for 14 days every 7 weeks in the DCOG-ALL-9 protocol. The 1107 children treated with the DCOG-ALL-7, DCOG-ALL-8 or DCOG-ALL-9 protocol were included and screened for infectious death during maintenance treatment (July 1988-July 2002). Seven of the 510 children died of severe infections during the maintenance phase of DCOG-ALL-9, compared to none of the 597 patients during the DCOG-ALL-7 and DCOG-ALL-8 protocols (1.37% versus 0.0%; p=0.013). Results from the current study suggest that repeated, prolonged exposure to dexamethasone results in an increase of lethal infections from 0% to 1.37%. In the dosing-schedule used, the advantage of dexamethasone may not outweigh the higher risk of infectious death.

The aim of this study was to investigate reproductive history and the prevalence of imminent ovarian failure (IOF) in female childhood cancer survivors. Reproductive history and ovarian function were evaluated by questionnaires (n = 124) and by measurement of follicle stimulating hormone (FSH) and oestradiol (E-2) levels (n = 93). IOF was defined as FSH > 10 IU/l or E-2 > 0.28 nmol/l on day 3 of the menstrual cycle, or FSH > 12.4 IU/l on day 7 of the pill-free interval. IOF was demonstrated in 22.6% of the participants and correlated with age at diagnosis (P

Abstract 2712 Acute Myeloid Leukemia (AML) bone marrow biopsies at diagnosis display an enhanced microvessel density (MVD), restoring to normal vessel counts when a complete remission has been achieved (de Bont et al, 2001; Padro et al, 2000). The enhanced MVD is correlated with increased expression of Vascular Endothelial Growth Factor (VEGFA), which is found to be a prognostic factor for therapeutic outcome in AML (de Bont et al, 2001, 2002; Aguayo et al, 1999). In the literature it has been described that the availability of VEGFA is related to different vascular morphology patterns in a xenograft mouse model (Lee et al., 2005). In this study we investigated the vascular morphology in AML bone marrow biopsies in relation to AML-derived VEGFA protein levels. Bone marrow biopsies (n=32) were stained for Factor VIII, a marker for Endothelial Cells, to enumerate the number of vessels. A significant (p95% of the NBM and AML remission biopsies had a vessel count below 13 microvessels/hpf, this value was taken as cut-off point for categorization into ‘low vessel count’ (13 or less) and ‘high vessel count' (more than 13). A ‘high vessel count' was detected in 75% (24/32) of the AML bone marrow biopsies at diagnosis. Since vessel stabilization requires pericyte coverage of the vascular sprouts, we studied the number of vessels positive for Smooth Muscle Actin (SMA), a marker for pericytes. In AML bone marrow biopsies at diagnosis 35% of vessels were pericyte coated versus 55% of vessels in NBM and AML remission (p=0.02). Interestingly, the percentage vessels coated with pericytes was significantly (p=0.04) higher in the biopsies with a ‘low vessel count' (45%) compared with the biopsies showing a ‘high vessel count' (29%), indicating that a high vessel density in AML is related to a more immature vessel status. To quantify the vasculature morphology, the vessel count was combined with a method to measure the vessel surface area (Chalkley count; Sie et al., 2010) (Fig. 1A). Based on the Chalkley count the AML bone marrow biopsies at diagnosis with ‘high vessel count' could be divided into two groups with abnormal vessels. The first group (37.5%) had a normal Chalkley count (group I in Fig. 1A) and was defined as ‘vessel hyperplasia', characterized by vessels with a predominantly large lumen and thin walls (Fig 1B). The second group (37.5%) had a Chalkley count below normal (group II in Fig. 1A) and was defined as ‘angiogenic sprouting', displaying a network of small vessels with thin walls, narrow lumen and branching (Fig.1C). Moreover, we found that high blast VEGFA protein levels were significantly (p=0.007) higher in the ‘vessel hyperplasia' group compared with the other defined groups. In conclusion, our study shows that heterogeneity in AML bone marrow vasculature exists and can be quantified using vessel count in combination with Chalkley count. Furthermore, the VEGFA protein levels excreted by AML blasts are related to the defined vessel morphology patterns. Clinical trials targeting the VEGF/VEGFR signaling pathway in patients with relapsed or refractory AML showed beneficial effects in only a subset of patients (Karp et al, 2004). It might be that adapting therapeutic approaches to bone marrow morphology will improve treatment outcome. Ongoing work investigating the response of anti-VEGFA therapies related to AML bone marrow vasculature will have to confirm this hypothesis. Fig.1. Morphology patterns in AML bone marrow biopsies. (A) Scatterplot representing the bone marrow vessel count and Chalkley count of AML at diagnosis, NBM and AML at remission. AML biopsies at diagnosis with a ‘low vessel count’ are displayed below the Y-axis reference line (13 microvessels/hpf), based on the fact that >95% of NBM and AML remission had a vessel count below 13 microvessels/hpf. The X-axis reference line divides AML biopsies at diagnosis with a ‘high vessel count' into two groups according to median Chalkley count of 5.4 in AML at diagnosis. The >95% Chalkley count of the NBM and AML remission biopsies sets an identical cut-off point. Group I, ‘vessel hyperplasia'>5.4; group II, ‘angiogenic sprouting' ≤5.4. Spearman's rho 0.15, p=0.42. (B) Representative picture of immunohistochemical staining for ‘vessel hyperplasia' and (C) ‘angiogenic sprouting'. Fig.1. Morphology patterns in AML bone marrow biopsies. (A) Scatterplot representing the bone marrow vessel count and Chalkley count of AML at diagnosis, NBM and AML at remission. AML biopsies at diagnosis with a ‘low vessel count’ are displayed below the Y-axis reference line (13 microvessels/hpf), based on the fact that >95% of NBM and AML remission had a vessel count below 13 microvessels/hpf. The X-axis reference line divides AML biopsies at diagnosis with a ‘high vessel count' into two groups according to median Chalkley count of 5.4 in AML at diagnosis. The >95% Chalkley count of the NBM and AML remission biopsies sets an identical cut-off point. Group I, ‘vessel hyperplasia'>5.4; group II, ‘angiogenic sprouting' ≤5.4. Spearman's rho 0.15, p=0.42. (B) Representative picture of immunohistochemical staining for ‘vessel hyperplasia' and (C) ‘angiogenic sprouting'. Disclosure: No relevant conflicts of interest to declare.

In 33 long-term survivors of lower extremity bone cancer quality-of-life data were studied following limb salvage compared to amputation. Self-report questionnaires, semistructured interviews and visual analog scales were used to measure psychoneurotic and somatical distress, activities of daily living, self-esteem, and adjustment to illness. Fourteen patients with limb salvage (age 13-56 years, median 24) and 19 patients with an amputation (age 21-53 years, median 27) were evaluated 2-17 years (median 10 years) after surgery. The differences between the two groups were not statistically significant. However, physical complaints were reported more often by limb salvage patients, whereas the amputees showed a trend toward lower self-esteem and isolation in social life, due to their disability. Both groups felt equal diminution of quality of life and disability as measured on the visual analog scale. These findings could support the cosmetic advantage of limb salvage compared to amputation.

Acute myeloid leukemia (AML) is a heterogeneous disease, characterized by a multitude of genetic events. Activating mutations in receptor tyrosine kinases have been identified in 50% of AML primary blasts, and deregulation of one or more signal transduction pathways including the JAK/STAT, RAS/Raf/MEK/ERK, and PI3K/AKT pathways is common (Kornblau et al., 2006). High-throughput procedures which generate comprehensive descriptions of cellular signaling without a priori assumptions in each sample, would enable us to directly assess a broader range of targets for future treatment strategies. In the present study we identified kinase activity profiles in 22 pediatric leukemia samples (6 acute myeloid leukemia, 9 acute lymphoid leukemia, 3 Philadelphia positive acute lymphoid leukemia and 5 chronic myeloid leukemia) and in various normal tissues such as colon and kidney. Peptide phosphorylation profiles were determined using the Pamchip® tyrosine kinase micro array system (Pamgene International B.V., ‘s Hertogenbosch, the Netherlands). This array consists of 144 peptides representing key phosphorylation sites of proteins known to be involved in signal transduction processes. We generated a comprehensive description of the phosphotyrosine proteome of all patient samples. Within the variety of profiles in the various leukemia samples, peptide corresponding with phosphorylation consensus sequences for MAP kinases showed remarkable high levels of phosphorylation, whereas in various normal tissue types substantial lower activity was observed on these substrates. These results imply activated MAPK signaling to be a prominent characteristic of leukemia as already described (Towatari et al., 1997). A differential phosphorylation pattern was seen for the RON peptide (macrophage stimulating 1 receptor (c-met-related tyrosine kinase)), only phosphorylated in one of the AML samples, 4 out of 5 CML samples and one Ph+ ALL sample. According to Phospho-ELM and the literature (Follenzi et al., 2000) this tyrosine kinase residue can be phosphorylated via autophosphorylation by RON kinase or transphosphorylation by MET kinase (met proto-oncogene (hepatocyte growth factor receptor)).To verify the role of MET kinase in AML, a cell survival assay was performed with the selective MET kinase inhibitor PHA 665752. Dose dependent decrease in cell survival was observed in three primary AML samples tested with LC50 concentrations ranging from 2 μM to 5 μM. In conclusion, this study describes a new high throughput technique to generate tyrosine phospho-proteomes or even kinome profiles of various leukemic samples in the future. With this technique we found MET to be a new therapeutic target in AML, and it demonstrates the importance of MAP kinase signaling in various leukemic samples. In the era of a rapidly increasing number of small molecule inhibitors this technique will enable us to rapidly identify new potential targets in different kinds of leukemia.