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Purpose: Activating mutations of the anaplastic lymphoma kinase (ALK) were recently described in neuroblastoma. We carried out a meta-analysis of 709 neuroblastoma tumors to determine their frequency and mutation spectrum in relation to genomic and clinical parameters, and studied the prognostic significance of ALK copy number and expression.Experimental Design: The frequency and type of ALK mutations, copy number gain, and expression were analyzed in a new series of 254 neuroblastoma tumors. Data from 455 published cases were used for further in-depth analysis.Results: ALK mutations were present in 6.9% of 709 investigated tumors, and mutations were found in similar frequencies in favorable [International Neuroblastoma Staging System (INSS) 1, 2, and 4S; 5.7%] and unfavorable (INSS 3 and 4; 7.5%) neuroblastomas (P = 0.087). Two hotspot mutations, at positions R1275 and F1174, were observed (49% and 34.7% of the mutated cases, respectively). Interestingly, the F1174 mutations occurred in a high proportion of MYCN-amplified cases (P = 0.001), and this combined occurrence was associated with a particular poor outcome, suggesting a positive cooperative effect between both aberrations. Furthermore, the F1174L mutant was characterized by a higher degree of autophosphorylation and a more potent transforming capacity as compared with the R1275Q mutant. Chromosome 2p gains, including the ALK locus (91.8%), were associated with a significantly increased ALK expression, which was also correlated with poor survival.Conclusions: ALK mutations occur in equal frequencies across all genomic subtypes, but F1174L mutants are observed in a higher frequency of MYCN-amplified tumors and show increased transforming capacity as compared with the R1275Q mutants. Clin Cancer Res; 16(17); 4353–62. ©2010 AACR.

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Supplementary Figures S1-S4 from Molecular Risk Stratification of Medulloblastoma Patients Based on Immunohistochemical Analysis of MYC, LDHB, and CCNB1 Expression

Purpose: Medulloblastoma is the most common malignant embryonal brain tumor in children. The current clinical risk stratification to select treatment modalities is not optimal because it does not identify the standard-risk patients with resistant disease or the unknown number of high-risk patients who might be overtreated with current protocols. The aim of this study is to improve the risk stratification of medulloblastoma patients by using the expression of multiple prognostic markers in combination with current clinical parameters.Experimental Design: Candidate prognostic markers were selected from literature or from medulloblastoma expression data. Selected genes were immunohistochemically analyzed for their prognostic value using medulloblastoma tissue arrays containing 124 well-characterized patient samples.Results: Protein expression analyses showed that the combined expression of three genes was able to predict survival in medulloblastoma patients. Low MYC expression identified medulloblastoma patients with a very good outcome. In contrast, concomitant expression of LDHB and CCNB1 characterized patients with a very poor outcome. Multivariate analyses showed that both expression of MYC and the LDHB/CCNB1 gene signature were strong prognostic markers independent of the clinical parameters metastasis and residual disease. Combined analysis of clinical and molecular markers enabled greater resolution of disease risk than clinical factors alone.Conclusions: A molecular risk stratification model for medulloblastoma patients is proposed based on the signature of MYC, LDHB, and CCNB1 expression. Combined with clinical variables, the model may provide a more accurate basis for targeting therapy in children with this disease.

We performed a systematic review to define the long-term health problems and optimal treatment strategy for patients with neuroblastoma with intraspinal extension. Of 685 identified studies, 28 were included in this review. The burden of long-term health problems is high; a median of 50% of patients suffered from neurological motor deficit, 34% from sphincter dysfunction, and 30% from spinal deformity. The currently available literature remains suboptimal as a guide for treatment of NBL with intraspinal extension. More well-designed, prospective studies are needed to determine the optimal treatment strategy.

To evaluate the prevalence of health problems in 5-year survivors treated for neuroblastoma (NBL) with intraspinal extension.Retrospective, single center cohort study (using data from Childhood Cancer Registry and medical records) of patients treated for NBL with intraspinal extension (between 1980 and 2007) who survived ≥ 5 years after diagnosis. Health problems were graded according to the Common Terminology Criteria for Adverse Events (CTCAEv.3.0).All eligible patients (n = 19) were included (n = 7 no neurological symptoms at diagnosis), median age at diagnosis was 1.2 years (0.6-10.8 years), and median follow-up time was 15.6 years (6.3-29.5 years). Ninety-five percent of survivors had ≥1 health problem and 48% of survivors had ≥4 health problem with a mean of 3.8 per survivor. Fifty-three percent of survivors had at least one severe (grade 3) or life-threatening/disabling (grade 4) health problem. The three most prevalent health problems were kyphosis and/or scoliosis (68% of patients), motor neuropathy (32% of patients), and sensory neuropathy (26% of patients). Of the 13 patients who underwent a laminectomy, 54% (seven of 13) developed a grade 3 and 23% (three of 13) developed a grade 4 health problem. Among six patients, without laminectomy, 17% developed (one of six) a grade 3 and in 17% developed (one of six) a grade 4 health problem.Ninety-five percent of 5-year survivors treated for a childhood intraspinal NBL have health problems. The high prevalence of grade 3 and 4 health problems (especially in the laminectomy group) emphasizes the importance of specialized long-term multidisciplinary follow-up and identifies optimal treatment with limited morbidity and maximal efficacy.

Self-reported data show differences in social outcomes (not being married/having a registered partnership; not living independently; using social benefits) for childhood cancer survivors compared with their peers. We aimed to determine differences in these social outcomes between survivors and the general population using national register data and explored associated risk factors.We performed medical record linkage between a single-centre cohort of 1768 ≥ 5-year survivors of childhood cancer (diagnosed 1966-2001) and two national registers (1999-2011) and obtained a random reference sample matched on gender and year of birth per survivor. We used multivariable logistic regression to calculate in adult survivors of childhood cancer (born before 1990) the odds of the specified social outcomes at the end of follow-up in both groups. Within the survivors, we analysed risk factors for the social outcomes.We retrieved data from 1283 adult childhood cancer survivors and 25 082 reference persons. Survivors had higher odds (odds ratio; 95% confidence interval) of not being married (1.2; 1.07-1.42), not living independently (1.7; 1.41-2.00) and using social benefits (2.3; 1.98-2.69) compared with reference persons. Radiotherapy to head and/or neck, and an original central nervous system tumour diagnosis negatively influenced all social outcomes examined in childhood cancer survivors.National register data show differences between social outcomes in childhood cancer survivors and the general population, especially for survivors treated with radiotherapy to head and/or neck and those originally diagnosed with central nervous system tumours. Development and implementation of effective targeted support strategies to improve social outcomes of childhood cancer survivors needs consideration. Copyright © 2015 John WileySons, Ltd.

In Malawi, preoperative chemotherapy for Wilms tumour is a logical strategy, but detailed information on toxicity and efficacy in such a resource limited setting has been unavailable.Patients diagnosed with a unilateral Wilms tumour received preoperative chemotherapy-a two-drug 4-week regimen for localized disease and 6 weeks of a three-drug regimen for metastatic disease. Estimated maximum tumour diameter, decrease in tumour size, resectability, stage distribution and haematological toxicity during therapy were documented.At diagnosis, 28% of 72 patients had an estimated maximum tumour diameter of more than 25 cm; 29% of patients had metastases. Eight children (11%) died during preoperative chemotherapy. More than half (59%) of the patients developed moderate neutropenia (neutrophils1.0 × 10(9) /L; CTC grade 3) and 27% severe neutropenia (CTC grade 4 neutrophils0.5 × 10.9/L). Grade 4 neutropenia occurred significantly more frequently in children receiving the three-drug regimen compared to the two-drug regimen; 50% (10/20) versus 15% (6/40) (P = 0.004). Fifty-seven percent of all patients had CTC grade 4 anaemia (Hb6.5 g/dL) during treatment. Most tumours (92%, 56/61) showed a response to chemotherapy but 14% (8/58) remained unresectable.Preoperative chemotherapy for Wilms tumour causes considerable haematological toxicity and treatment-related mortality in malnourished Malawian children. A significant number of children have unresectable disease despite preoperative chemotherapy. To reduce treatment related mortality, consideration should be given to starting treatment with reduced doses in acutely malnourished patients.

The aim of the current study is to investigate the effectiveness of an intervention that provides health-related quality of life (HRQOL) scores of the patient (the QLIC-ON PROfile) to the pediatric oncologist.Children with cancer participated in a sequential cohort intervention study: intervention N = 94, control N = 99. Primary outcomes of effectiveness were communication about HRQOL domains (t-test, Mann-Whitney U-test) and identification of HRQOL problems (chi-squared test). Secondary outcomes were satisfaction (multilevel analysis), referrals (chi-squared test), and HRQOL (multilevel analysis).The QLIC-ON PROfile increased discussion of emotional functioning (control M = 32.9 vs. intervention M = 47.4, P0.05) and psychosocial functioning (M = 56.9 vs. M = 63.8, P0.05). Additionally more emotional problems remained unidentified in the control compared to the intervention group, for example, anger (control 26% vs. intervention 3%, P0.01), fear (14% vs. 0%, P0.01), and sadness (26% vs. 0%, P0.001). The intervention had no effect on satisfaction and referrals, but did improve HRQOL of patients 5-7 years of age with respect to self-esteem (P0.05), family activities (P0.05), and psychosocial functioning (P0.01).We conclude that a PRO is a helpful tool for systematic monitoring HRQOL of children with cancer, without lengthening the duration of the consultation. It is recommended to be implemented in clinical practice.