Antoinette Y. N. Schouten-van Meeteren

WHITE MATTER FRACTIONAL ANISOTROPY CORRELATES WITH SPEED OF PROCESSING AND MOTOR SPEED IN YOUNG CHILDHOOD CANCER SURVIVORS

PURPOSE To determine whether childhood medulloblastoma and acute lymphoblastic leukemia (ALL) survivors have decreased white matter fractional anisotropy (WMFA) and whether WMFA is related to the speed of processing and motor speed. METHODS AND MATERIALS For this study, 17 patients (6 medulloblastoma, 5 ALL treated with high-dose methotrexate (MTX) (4 x 5 g/m(2)) and 6 with low-dose MTX (3 x 2 g/m(2))) and 17 age-matched controls participated. On a 3.0-T magnetic resonance imaging (MRI) scanner, diffusion tensor imaging (DTI) was performed, and WMFA values were calculated, including specific regions of interest (ROIs), and correlated with the speed of processing and motor speed. RESULTS Mean WMFA in the patient group, mean age 14 years (range 8.9 - 16.9), was decreased compared with the control group (p = 0.01), as well as WMFA in the right inferior fronto-occipital fasciliculus (IFO) (p = 0.03) and in the genu of the corpus callosum (gCC) (p = 0.01). Based on neurocognitive results, significant positive correlations were present between processing speed and WMFA in the splenium (sCC) (r = 0.53, p = 0.03) and the body of the corpus callosum (bCC) (r = 0.52, p = 0.03), whereas the right IFO WMFA was related to motor speed (r = 0.49, p < 0.05). CONCLUSIONS White matter tracts, using a 3.0-T MRI scanner, show impairment in childhood cancer survivors, medulloblastoma survivors, and also those treated with high doses of MTX. In particular, white matter tracts in the sCC, bCC and right IFO are positively correlated with speed of processing and motor speed.

Prevalence and risk factors of radiation-induced growth hormone deficiency in childhood cancer survivors: A systematic review

BACKGROUND Growth hormone deficiency (GHD) is usually the first and most frequent endocrine problem occurring after cranial radiotherapy (CRT). The aim of this systematic review was to evaluate the existing evidence of the prevalence and risk factors of radiation-induced GHD in childhood cancer survivors. METHODS MEDLINE, EMBASE and CENTRAL were searched for studies reporting on radiation-induced GHD in childhood cancer survivors. Information about study characteristics, prevalence and risk factors was abstracted and the quality of each study was assessed. A meta-regression analysis was performed. RESULTS The prevalence of radiation-induced GHD was estimated in 33 studies. Most studies had methodological limitations. The prevalence varied considerably between 0% and 90.9%. Selecting only the studies with adequate peak GH cut-off limits (<5 microg/L) resulted in 3 studies. In these studies the prevalence ranged from 29.0% to 39.1%, with a pooled prevalence of 35.6%. Higher CRT dose and longer follow-up time have been suggested to be the main risk factors of GHD by studies included in this review. The meta-regression analysis showed that the wide variation in the prevalence of GHD could be explained by differences in maximal CRT dose. CONCLUSIONS GHD is a frequent consequence after CRT in childhood cancer survivors. The prevalence of radiation-induced GHD ranged from 29.0% to 39.1% when selecting only studies with adequate peak GH cut-off limits. Higher CRT dose and longer follow-up time are the main risk factors. More well-designed studies are needed to accurately estimate the prevalence of GHD and to define the exact CRT threshold dose.

Neurocognitive consequences of a paediatric brain tumour and its treatment: a meta-analysis.

Aim  This meta‐analysis provides a systematic review of studies into intellectual and attentional functioning of paediatric brain tumour survivors (PBTS) as assessed by two widely used measures: the Wechsler Intelligence Scale for Children (3rd edition; WISC‐III) and the Conners’ Continuous Performance Test (CPT).

Cystatin C more accurately detects mildly impaired renal function than creatinine in children receiving treatment for malignancy

Monitoring of renal function is crucial in pediatric oncology. The use of creatinine to estimate glomerular filtration rate (GFR) is hampered by its dependency on muscle mass. Muscle wasting is common in children with cancer, leading to overestimation of GFR. Data on cystatin C are sparse in pediatric oncology, although this marker could be particularly useful in this population.

Renal Dysfunction and Elevated Blood Pressure in Long-Term Childhood Cancer Survivors

BACKGROUND AND OBJECTIVES Little is known about renal function and blood pressure (BP) in long-term childhood cancer survivors. This cross-sectional study evaluated prevalence of these outcomes and associated risk factors in long-term childhood cancer survivors at their first visit to a specialized outpatient clinic. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Estimated GFR; percentages of patients with albuminuria, hypomagnesemia, and hypophosphatemia; and BP were assessed in 1442 survivors ≥5 years after diagnosis. Multivariable logistic regression analyses were used to estimate effect of chemotherapy, nephrectomy, and radiation therapy on the different outcomes. RESULTS At a median age of 19.3 years (interquartile range, 15.6-24.5 years), 28.1% of all survivors had at least one renal adverse effect or elevated BP. The median time since cancer diagnosis was 12.1 years (interquartile range, 7.8-17.5 years). High BP and albuminuria were most prevalent, at 14.8% and 14.5%, respectively. Sixty-two survivors (4.5%) had an estimated GFR <90 ml/min per 1.73 m(2). Survivors who had undergone nephrectomy had the highest risk for diminished renal function (odds ratio, 8.6; 95% confidence interval [CI], 3.4-21.4). Combined radiation therapy and nephrectomy increased the odds of having elevated BP (odds ratio, 4.92; 95% CI, 2.63-9.19), as did male sex, higher body mass index, and longer time since cancer treatment. CONCLUSION Almost 30% of survivors had renal adverse effects or high BP. Therefore, monitoring of renal function in high-risk groups and BP in all survivors may help clinicians detect health problems at an early stage and initiate timely therapy to prevent additional damage.

At what age could screening for familial retinoblastoma be stopped? A register based study 1945–98

AIM To evaluate until what age children in families with retinoblastoma should be screened. METHODS A register based cohort (n= 685) study of Dutch retinoblastoma patients (1945–1998). The records of all familial hereditary retinoblastoma patients from 1945 were reviewed and the age at diagnosis and either they were screened from birth determined. RESULTS 75 patients had the familial hereditary form of retinoblastoma. The mean age at diagnosis in patients with fundus screening (n=50) from birth on was 4.9 months (median 1.9 months; range 1 day to 48 months). Thus, 4 years was the latest onset of familial retinoblastoma properly evaluated from birth. This mean age was significantly different (p<0.0001) from the mean age at diagnosis in patients without fundus screening (n=25) from birth (mean 17.2 months; median 10.0 months; range 1.5–63.0 months). CONCLUSIONS Ophthalmological screening of children and sibs at risk for familial hereditary retinoblastoma is recommended until the age of 4 years in order to detect retinoblastoma as early as possible.

Sleep disorders in children after treatment for a CNS tumour

The long‐term survival of children with a central nervous system (CNS) tumour is improving. However, they experience late effects, including altered habits and patterns of sleep. We evaluated the presence and type of sleep disorders and daytime sleepiness in these children, and its associations with clinical characteristics and daily performance (fatigue and psychosocial functioning). In a cross‐sectional study at the outpatient clinic of the Emma Children’s Hospital AMC (February–June 2010), sleep, fatigue and psychosocial functioning were analysed in 31 CNS tumour patients (mean age: 11.8 years; 20 boys) and compared with 78 patients treated for a non‐CNS malignancy (mean age: 9.7 years; 41 boys) and norm data. Questionnaires applied were the Sleep Disorder Scale for Children, the Epworth Sleepiness Scale, the Pediatric Quality of Life Inventory, and the Strengths and Difficulties Questionnaire. Sleeping habits and endocrine deficiencies were assessed with a self‐developed questionnaire. Increased somnolence was found in CNS tumour patients compared with those with a non‐CNS malignancy (8.8 ± 2.8 versus 7.5 ± 2.7; P < 0.05). Both patient groups reported more problems (P < 0.01) than the norm with initiating and maintaining sleep. No specific risk factors were identified for a sleep disorder in CNS tumour patients, but their excessive somnolence was correlated with lower fatigue related quality of life (QoL) (r = −0.78, P < 0.001) and worse psychosocial functioning (r = 0.63, P < 0.001). In conclusion, children treated for a CNS tumour have increased somnolence, significantly increasing fatigue and worsening daily functioning. Further investigation should focus on possibilities to improve sleep quality and diminish fatigue.

Subgroup-specific localization of human medulloblastoma based on pre-operative MRI

cochlear nucleus [2, 5], while WNT-MBs originate from dorsal brainstem precursors [1]. In order to unravel a possible relation between human MB biology and localization, and to provide novel hints regarding the cellular origin of MB, we characterized localization patterns of 71 human MBs using pre-operative MrI. Molecular MB subgrouping was established via gene expression profiling as described [4] and MrIs were analyzed blinded. Cohort details are Medulloblastoma (MB) is a group of malignant pediatric brain tumors arising in the posterior fossa. These tumors are classified into four molecular subgroups, namely WNT-, sHH-, Group 3and Group 4-MB [6]. In mice, sHH-MBs arise from granule cell precursors of the cerebellum and the

Dose-Effect Relationships for Adverse Events After Cranial Radiation Therapy in Long-term Childhood Cancer Survivors

PURPOSE To evaluate the prevalence and severity of clinical adverse events (AEs) and treatment-related risk factors in childhood cancer survivors treated with cranial radiation therapy (CRT), with the aim of assessing dose-effect relationships. METHODS AND MATERIALS The retrospective study cohort consisted of 1362 Dutch childhood cancer survivors, of whom 285 were treated with CRT delivered as brain irradiation (BI), as part of craniospinal irradiation (CSI), and as total body irradiation (TBI). Individual CRT doses were converted into the equivalent dose in 2-Gy fractions (EQD(2)). Survivors had received their diagnoses between 1966 and 1996 and survived at least 5 years after diagnosis. A complete inventory of Common Terminology Criteria for Adverse Events grade 3.0 AEs was available from our hospital-based late-effect follow-up program. We used multivariable logistic and Cox regression analyses to examine the EQD(2) in relation to the prevalence and severity of AEs, correcting for sex, age at diagnosis, follow-up time, and the treatment-related risk factors surgery and chemotherapy. RESULTS There was a high prevalence of AEs in the CRT group; over 80% of survivors had more than 1 AE, and almost half had at least 5 AEs, both representing significant increases in number of AEs compared with survivors not treated with CRT. Additionally, the proportion of severe, life-threatening, or disabling AEs was significantly higher in the CRT group. The most frequent AEs were alopecia and cognitive, endocrine, metabolic, and neurologic events. Using the EQD(2), we found significant dose-effect relationships for these and other AEs. CONCLUSION Our results confirm that CRT increases the prevalence and severity of AEs in childhood cancer survivors. Furthermore, analyzing dose-effect relationships with the cumulative EQD(2) instead of total physical dose connects the knowledge from radiation therapy and radiobiology with the clinical experience.

SIOP PODC adapted treatment recommendations for standard-risk medulloblastoma in low and middle income settings

Effective treatment of children with medulloblastoma requires a functioning multi‐disciplinary team with adequate neurosurgical, neuroradiological, pathological, radiotherapy and chemotherapy facilities and personnel. In addition the treating centre should have the capacity to effectively screen and manage any tumour and treatment‐associated complications. These requirements have made it difficult for many low and middle‐income countries (LMIC) centres to offer curative treatment. This article provides management recommendations for children with standard‐risk medulloblastoma (localised tumours in children over the age of 3–5 years) according to the level of facilities available. Pediatr Blood Cancer 2015;62:553–564.