Risk-adapted approach for fever and neutropenia in paediatric cancer patients--a national multicentre study.

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.

A longitudinal case-control study on goals in adolescents with cancer.

OBJECTIVE: This study examined whether: (1) the goals of adolescents with cancer at 3 months post-diagnosis (T1) and healthy peers differed in terms of content, valuation, and abstraction level, (2) the content, valuation and abstraction level of the goals of the adolescents with cancer differed between 3 and 12 months post-diagnosis (T2). METHODS: Thirty-three adolescents with cancer and 66 matched controls completed the Personal Project Analysis Inventory. After nine months, the adolescents with cancer completed the measure again. RESULTS: Compared to controls, adolescents with cancer at 3 months post-diagnosis (T1) reported more intrinsic than extrinsic goals, appraised intrinsic goals as more important than extrinsic goals and reported more concrete goals. Within the adolescents with cancer, the content, valuation and abstraction level of the goals did not differ between T1 and T2. CONCLUSIONS: Adolescents recently diagnosed with cancer set different types of goals than healthy peers and continue to set these types of goals until one year post-diagnosis. Future research can help determine how the personal goals of adolescents with cancer develop in the long term and to what extent personal goal setting during cancer influences the attainment of age-graded developmental tasks and well-being.

Effects of communication styles on marital satisfaction and distress of parents of pediatric cancer patients: a prospective longitudinal study.

OBJECTIVE: The aim of this study was to examine the longitudinal effects of communication styles on marital satisfaction and distress of parents of children treated for cancer. METHODS: Marital dissatisfaction (Maudsley Marital Questionnaire), intimacy, avoidance, destructive and incongruent communication (Communication Skills Inventory) and psychological distress (General Health Questionnaire) were assessed in 115 parents of pediatric cancer patients shortly after diagnosis (T1) and 5 years later (T2). RESULTS: Only mothers' marital dissatisfaction increased significantly over time. No gender differences in dissatisfaction were found. Mothers had a significantly higher lack of intimacy score than fathers. All T1 communication styles were significantly univariately related to fathers' and mothers' T2 marital dissatisfaction, while not to T2 distress. Mothers' T1 marital dissatisfaction accounted for 67% and fathers' for 12% in the explained variance of T2 dissatisfaction. T1 destructive communication uniquely affected fathers' T2 marital dissatisfaction and T1 avoidant communication that of mothers. CONCLUSIONS: Five years after cancer diagnosis in their children, the quality of parents' marital relationships seemed largely unchanged. Parents' use of communication skills at diagnosis appeared to have limited effect on their marital dissatisfaction and no effect on their distress 5 years later. While avoidant communication seemed indicative of mothers' marital distress, fathers' seemed affected by destructive communication.

Changes in nutritional status in childhood cancer patients: a prospective cohort study.

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.

Providing care to a child with cancer: a longitudinal study on the course, predictors, and impact of caregiving stress during the first year after diagnosis.

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.

Social competence in children with brain disorders: a meta-analytic review.

Social competence, i.e. appropriate or effective social functioning, is an important determinant of quality of life. Social competence consists of social skills, social performance and social adjustment. The current paper reviews social skills, in particular emotion recognition performance and its relationship with social adjustment in children with brain disorders. In this review, normal development and the neuro-anatomical correlates of emotion recognition in both healthy children and adults and in various groups of children with brain disorders, will be discussed. A systematic literature search conducted on PubMed, yielded nine papers. Emotion recognition tasks were categorized on the basis of task design and emotional categories to ensure optimal comparison across studies before an explorative meta-analysis was conducted. This meta-analytic review suggests that children with brain disorders show impaired emotion recognition, with the recognition of sad and fearful expressions being most impaired. Performance did not seem to be related to derivative measures of social adjustment. Despite the limited number of studies on a variety of brain disorders and control groups, outcomes were quite consistent across analyses and corresponded largely with the existing literature on development of emotion recognition in typically developing children. More longitudinal prospective studies on emotion recognition are needed to gain insight into recovery and subsequent development of children with distinct brain disorders. This will aid development, selection and implementation of interventions for improvement of social competence and quality of life in children with a brain disorder.

Exploring the response shift phenomenon in childhood patients with cancer and its effect on health-related quality of life.

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.

Bacteria causing bacteremia in pediatric cancer patients presenting with febrile neutropenia--species distribution and susceptibility patterns.

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.

Impaired long-term expansion and self-renewal potential of pediatric acute myeloid leukemia-initiating cells by PTK787/ZK 222584.

Although most children with acute myeloid leukemia (AML) achieve complete remission, the relapse rate is 30% to 40%. Because it is thought that leukemia-initiating cells (LIC) are responsible for AML relapses, targeting these cells might improve outcome. Treatment of pediatric AML blasts with the receptor tyrosine kinase (RTK) inhibitor PTK787/ZK 222584 (PTK/ZK) induces cell death in vitro. However, the role of PTK/ZK inhibition on outgrowth of (pediatric) LICs is unknown. In this study, we cultured CD34+ cells from pediatric patients with AML on MS5 stromal cells in long-term cocultures. In analogy to adult AML, long-term expansion of leukemic cells up to 10 weeks could be generated in 9 of 13 pediatric AMLs. Addition of PTK/ZK to long-term cocultures significantly inhibited leukemic expansion in all samples, ranging from 4% to 80% growth inhibition at week 5 compared with untreated samples. In 75% of the samples, the inhibitory effect was more pronounced at week 10. Proteome profiler array analysis of downstream kinases revealed that PTK/ZK reduced activation of PI3K/Akt kinase signaling. Although main targets of PTK/ZK are VEGF receptors (VEGFR), no effect was seen on outgrowth of LICs when cultured with bevacizumab (monoclonal VEGFA-antibody), specific antibodies against VEGFR2 or VEGFR3, or exposed to stroma-derived VEGFA. These data suggest that the effect of PTK/ZK on LICs is not only dependent on inhibition of VEGFA/VEGFR signaling. Taken together, our data elucidated antileukemic properties of PTK/ZK in long-term expansion cultures, and suggest that targeting multiple RTKs by PTK/ZK might be a potential effective approach in eradicating (pediatric) LICs.

Dispositional optimism in adolescents with cancer: differential associations of optimism and pessimism with positive and negative aspects of well-being.

OBJECTIVES: Dispositional optimism is often considered to be a unidimensional construct. Recent studies suggest, however, that optimism and pessimism are separate dimensions. In this study we investigated two issues. First, the levels of optimism and pessimism in adolescents with cancer compared with healthy controls and second, the individual effects of optimism and pessimism on concurrent and longitudinal well-being. DESIGN: A matched case-control design was used to examine whether adolescents with cancer and healthy adolescents differed with regard to optimism and pessimism. The second part of the study was employed in a prospective design with assessments in the patient group at 3 and 6 months post-diagnosis. METHODS: Thirty-three adolescents with cancer (3 months post-diagnosis) and 66 matched controls completed a measure on dispositional optimism (i.e., optimism and pessimism). In addition, patients completed measures on positive and negative aspects of well-being at 3 and 6 months post-diagnosis. RESULTS: Although adolescents with cancer were not more optimistic than their healthy peers, they were significantly less pessimistic. Zero order and semi-partial correlations showed that optimism and pessimism are related to different aspects of well-being. Specifically, we found a cohesive pattern in which optimism predicts positive aspects and pessimism negative aspects of well-being. CONCLUSIONS: The high levels of overall optimism often found in patients with cancer might in fact result from low pessimism instead of high optimism. Furthermore, as our study shows that optimism and pessimism are differentially associated with aspects of well-being, it provides strong support for the bidimensionality of dispositional optimism.

EphB2 activity plays a pivotal role in pediatric medulloblastoma cell adhesion and invasion.

Eph/ephrin signaling has been implicated in various types of key cancer-enhancing processes, like migration, proliferation, and angiogenesis. In medulloblastoma, invading tumor cells characteristically lead to early recurrence and a decreased prognosis. Based on kinase-activity profiling data published recently, we hypothesized a key role for the Eph/ephrin signaling system in medulloblastoma invasion. In primary medulloblastoma samples, a significantly higher expression of EphB2 and the ligand ephrin-B1 was observed compared with normal cerebellum. Furthermore, medulloblastoma cell lines showed high expression of EphA2, EphB2, and EphB4. Stimulation of medulloblastoma cells with ephrin-B1 resulted in a marked decrease in in vitro cell adhesion and an increase in the invasion capacity of cells expressing high levels of EphB2. The cell lines that showed an ephrin-B1-induced phenotype possessed increased levels of phosphorylated EphB2 and, to a lesser extent, EphB4 after stimulation. Knockdown of EphB2 expression by short hairpin RNA completely abolished ephrin ligand-induced effects on adhesion and migration. Analysis of signal transduction identified p38, Erk, and mTOR as downstream signaling mediators potentially inducing the ephrin-B1 phenotype. In conclusion, the observed deregulation of Eph/ephrin expression in medulloblastoma enhances the invasive phenotype, suggesting a potential role in local tumor cell invasion and the formation of metastases.

The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia.

BACKGROUND: PI3K/AKT pathway mutations are found in T-cell acute lymphoblastic leukemia, but their overall impact and associations with other genetic aberrations is unknown. PTEN mutations have been proposed as secondary mutations that follow NOTCH1-activating mutations and cause cellular resistance to γ-secretase inhibitors. DESIGN AND METHODS: The impact of PTEN, PI3K and AKT aberrations was studied in a genetically well-characterized pediatric T-cell leukemia patient cohort (n=146) treated on DCOG or COALL protocols. RESULTS: PTEN and AKT E17K aberrations were detected in 13% and 2% of patients, respectively. Defective PTEN-splicing was identified in incidental cases. Patients without PTEN protein but lacking exon-, splice-, promoter mutations or promoter hypermethylation were present. PTEN/AKT mutations were especially abundant in TAL- or LMO-rearranged leukemia but nearly absent in TLX3-rearranged patients (P=0.03), the opposite to that observed for NOTCH1-activating mutations. Most PTEN/AKT mutant patients either lacked NOTCH1-activating mutations (P=0.006) or had weak NOTCH1-activating mutations (P=0.011), and consequently expressed low intracellular NOTCH1, cMYC and MUSASHI levels. T-cell leukemia patients without PTEN/AKT and NOTCH1-activating mutations fared well, with a cumulative incidence of relapse of only 8% versus 35% for PTEN/AKT and/or NOTCH1-activated patients (P=0.005). CONCLUSIONS: PI3K/AKT pathway aberrations are present in 18% of pediatric T-cell acute lymphoblastic leukemia patients. Absence of strong NOTCH1-activating mutations in these cases may explain cellular insensitivity to γ-secretase inhibitors.

Malnutrition in childhood cancer patients: a review on its prevalence and possible causes.

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.

Different outcome in older children with acute lymphoblastic leukemia with different treatment protocols in the Netherlands.

BACKGROUND: From 1991 until 2004 children with acute lymphoblastic leukemia (ALL) in the Netherlands were treated according to protocols ALL-8 and ALL-9 which were based on different principles. An earlier study showed that the outcome of adolescents highly differed on these protocols. PROCEDURE: In this retrospective study, we analyzed whether the outcome of older children 10-15 years of age at diagnosis differed between the Berlin-Frankfurt-Münster (BFM)-based ALL-8 regimen and the ALL-9 regimen. Two hundred fifty-four older children who were treated according to protocol ALL-8 (n = 82) or ALL-9 (n = 172) were included in the analysis. RESULTS: A higher 5-year event-free survival (EFS) rate was found for patients treated according to ALL-8 compared to ALL-9 (79 ± 5% vs. 65 ± 4%, P = 0.02). Patient characteristics did not differ except for a slightly higher age in ALL-8. Therefore, additional analyses were done including only patients who were 12-15 years of age. In this age group there was also a difference in the 5-year EFS (82 ± 5% vs. 61 ± 5%, P = 0.00) as well as in the 5-year overall survival rate; 89 ± 4% compared to 68 ± 5%, respectively (P = 0.01). Major difference between protocols was the use of a consolidation and reinduction/intensification course and higher cumulative doses of asparaginase, methotrexate, and anthracyclines in ALL-8. CONCLUSIONS: Children 10-15 years of age have been undertreated with the ALL-9 regimen and benefit by intensive treatment components as used in ALL-8. We recommend using BFM-based protocols for these older children with ALL.

Coping and its effect on psychological distress of parents of pediatric cancer patients: a longitudinal prospective study.

OBJECTIVE: This prospective 5-year longitudinal study examined the use of coping styles of fathers and mothers of pediatric cancer patients over time and the prospective effects of coping on distress. METHODS: Psychological distress (General Health Questionnaire) and the use of seven coping styles (Utrecht Coping List: active problem focussing, palliative and passive reaction patterns, avoidance, social support seeking, expression of emotions, and comforting cognition) were assessed in 115 parents shortly after diagnosis, 6 and 12 months, and 5 years later. RESULTS: At diagnosis, parents' use of coping styles did not differ from the norm population except more frequent use of support seeking. No significant change over time was found in a palliative reaction pattern. Support seeking declined and emotional expression increased linearly, whereas use of the remaining coping styles decreased, followed by an increase. At 5 years, parents' use differed from the norm population only in less use of expression of emotions and comforting cognitions. Initial coping use significantly predicted fathers' future distress at 6 and 12 months but not at 5 years. This was not found for mothers. Changes in coping were significantly associated with both parents' changes in distress only during the first year. Increased passive reaction pattern and social support seeking were the risk factors for mothers. Increased avoidance, a passive reaction pattern, expression of emotions, and decreased active problem focussing formed the risk factors for fathers. CONCLUSION: Findings illustrate that coping seems to be a situation-specific process and that coping predictors vary as a function of parents' gender.

High acute myeloid leukemia derived VEGFA levels are associated with a specific vascular morphology in the leukemic bone marrow.

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.

Repression of vascular endothelial growth factor expression by the runt-related transcription factor 1 in acute myeloid leukemia.

VEGFA is considered one of the most important regulators of tumor-associated angiogenesis in cancer. In acute myeloid leukemia (AML) VEGFA is an independent prognostic factor for reduced overall and relapse-free survival. Transcriptional activation of the VEGFA promoter, a core mechanism for VEGFA regulation, has not been fully elucidated. We found a significant (P < 0.0001) inverse correlation between expression of VEGFA and AML1/RUNX1 in a large set of gene expression array data. Strikingly, highest VEGFA levels were demonstrated in AML blasts containing a t(8;21) translocation, which involves the AML1/RUNX1 protein (AML1/ETO). Overexpression of AML1/RUNX1 led to downregulation of VEGFA expression, whereas blocking of AML1/RUNX1 with siRNAs resulted in increased VEGFA expression. Cotransfection of AML1/RUNX1 and VEGFA promoter luciferase promoter constructs resulted in a decrease in VEGFA promoter activity. ChIP analysis shows a direct binding of AML1/RUNX1 to the promoter of VEGFA on three AML1/RUNX1 binding sites. Silencing of AML1/ETO caused a decrease in VEGFA mRNA expression and a decrease in secreted VEGFA protein levels in AML1/ETO-positive Kasumi-1 cells. Taken together, these data pinpoint to a model whereby in normal cells AML1/RUNX1 acts as a repressor for VEGFA, while in AML cells VEGFA expression is upregulated due to AML1/RUNX1 aberrations, for example, AML1/ETO. In conclusion, these observations give insight in the regulation of VEGFA at the mRNA level in AML.