Health-related quality of life after completion of successful treatment for childhood cancer.

BACKGROUND: Previous studies have assessed health-related quality of life (HRQOL) during several treatment stages in children with cancer, but there is limited knowledge about HRQOL shortly after completing therapy. This study determined HRQOL of children with cancer shortly after the end of successful treatment compared with normative values. PROCEDURE: Several age-specific HRQOL questionnaires were administered: the ITQOL (generic, proxy-report, 0-4 years), CHQ PF 50 (generic, proxy-report, 5-7 years), Kidscreen (generic, self-report, 8-18 years) and Disabkids (chronic generic, self-report, 8-18 years). RESULTS: Children with cancer (N = 191, mean age 9.25, SD 5.06, 47.1% female) participated. Physical well-being was affected for all ages. Compared to normative values 0- to 7-year-olds were rated significantly lower on the majority of the scales. In addition, 12- to 18-year-olds had significantly better HRQOL than the norm on social scales. Compared to chronically ill norms, 8- to 18-year-olds demonstrated no differences, except for 12- to 18-year-olds who experienced significantly more physical limitations. Additionally, we found that HRQOL of parents of 0- to 7-year-olds was poorer than the norm. CONCLUSION: HRQOL in children with cancer and their parents can be impaired compared with the norm. Therefore, HRQOL should be monitored in clinical practice to make paediatric oncologists aware of these problems. For young children, we recommend checking whether certain HRQOL problems can be explained by parental worries. For older children and adolescents, paediatric oncologists need to consider social desirability and the child's adaptive style.

Profiling of high-grade central osteosarcoma and its putative progenitor cells identifies tumourigenic pathways.

BACKGROUND: Osteosarcoma is the most prevalent primary malignant bone tumour in children and young adults, with poor survival in 40% of patients. To identify the signalling pathways involved in tumourigenesis, we compared gene expression in osteosarcoma with that in its presumed normal counterparts. METHODS: Genome-wide expression profiles were generated from 25 high-grade central osteosarcoma prechemotherapy biopsies, 5 osteoblastomas, 5 mesenchymal stem cell (MSC) populations and these same MSCs differentiated into osteoblasts. Genes that were differentially expressed were analysed in the context of the pathways in which they function using the GenMAPP programme. RESULTS: MSCs, osteoblasts, osteoblastomas and osteosarcomas clustered separately and thousands of differentially expressed genes were identified. The most significantly altered pathways are involved in cell cycle regulation and DNA replication. Several upstream components of the Wnt signalling pathway are downregulated in osteosarcoma. Two genes involved in degradation of beta-catenin protein, the key effectors of Wnt signalling, Axin and GSK3-beta, show decreased expression, suggesting that Wnt signalling is no longer under the control of regular signals. Comparing benign osteoblastomas with osteosarcomas identified cell cycle regulation as the most prominently changed pathway. CONCLUSION: These results show that upregulation of the cell cycle and downregulation of Wnt signalling have an important role in osteosarcoma genesis. Gene expression differences between highly malignant osteosarcoma and benign osteoblastoma involve cell cycle regulation.

Overexpression of the HER-2 oncogene does not play a role in high-grade osteosarcomas.

The aim of our study was to determine whether or not the tyrosine kinase receptor, HER2 (also known as ErbB2/Her2/neu), is overexpressed in human osteosarcomas (OS). We studied 15 biopsy and 18 resection specimens at the mRNA and protein levels. HER2 status in the OS specimens was assessed by immunohistochemistry (IHC) and quantitative Real-Time Polymerase chain reaction (PCR). In moderately immunopositive cases fluorescent in situ hybridisation (FISH) analysis was used in order to identify any possible gene amplification. 27 samples were evaluable for IHC and only 1 case showed a moderately positive membrane staining. The remaining samples showed no staining or focal cytoplasmic staining (2 samples). In the moderately positive case, FISH analysis showed no HER-2 gene amplification. There was also no overexpression of HER2 mRNA suggesting this sample was a false-positive immunostain. HER2 mRNA expression was present in all samples at a similar level to that in the breast cancer cell line, MCF7, which does not overexpress HER2 and was used as a negative control. In conclusion, this study shows that HER2 mRNA or membranous HER2 protein overexpression is absent in human OS. We noted various inconsistencies in previous published studies, with regard to methodology and the interpretation of the results based on poor methodology. We therefore conclude that the positive data with regard to HER2 overexpression reported in these previous studies is not reliable. Our results suggest that the monoclonal antibody trastuzumab (Herceptin(R)), directed against the HER2-receptor, is not likely to be an effective therapeutic agent in OS.

[Cyclic neutropenia and treatment with granulocyte colony-stimulating factor (G-CSF)]. / Cyclische neutropenie en behandeling met granulocyt-kolonie-stimulerende factor (G-CSF).

A patient with familial cyclic neutropenia (CN) is presented. In a son of a mother with known CN, periodic neutropenia was demonstrated a few months after birth. At 18 years of age, the boy had recurrent episodes of cervical lymphadenopathy, complicated by an abscess. Periodic treatment with granulocyte-colony stimulating factor (G-CSF) was initiated, and since then, he hardly had any symptoms and clinically showed substantial improvement. Based on in-vitro colony assays of patients with CN, it is nowadays suggested that a disturbance in growth factor receptor binding or post-receptor signal transduction is the cause of this rare benign haematological disorder.

Technetium-99m dimercaptosuccinic acid and ifosfamide tubular dysfunction in children with cancer.

Quantitative 99mTc-dimercaptosuccinic acid (99mTc-DMSA) renal scintigraphy was used to asses ifosfamide-induced changes in renal function in 11 children who received chemotherapy for various malignancies. Serial measurements of absolute 99mTc-DMSA renal uptake, calculated on conjugated views, were performed during and after chemotherapy. Data of 37 studies obtained before and at different cumulative dose levels of ifosfamide were analysed in relation to clinical and biochemical parameters. A highly significant relationship between 99mTc-DMSA uptake and cumulative ifosfamide dose was found (P < 0.001). The most frequently observed abnormal pattern on scintigraphic images was decreased kidney uptake together with increased accumulation in bladder. 99mTc-DMSA uptake was more consistent than beta 2-microglobulin values in urine and more sensitive than quantitative hyperaminoaciduria and tubular resorption of phosphate for the detection of ifosfamide-induced tubular dysfunction. 99mTc-DMSA uptake was decreased in both patients with and patients without clinical toxicity. Persistently reduced 99mTc-DMSA uptake was observed in four patients during follow-up; in one of them, who was asymptomatic after ifosfamide therapy, sudden onset of Fanconi syndrome was observed when he was retreated with carboplatin 1 year later. It is concluded that 99mTc-DMSA renal scintigraphy is a suitable method to assess progressive ifosfamide-induced tubular injury whereas scintigraphic imaging is helpful for interpreting renal uptake changes. The test is able to detect subclinical injury and may potentially predict high risk at retreatment.

Radiation injury in the human kidney: a prospective analysis using specific scintigraphic and biochemical endpoints.

Renal function was prospectively analyzed in 26 evaluable patients, irradiated to various doses on their kidneys for neoplastic disease. Glomerular function was assessed by 99mTc-DTPA renography, creatinine clearance, and serum beta 2-microglobulin, whereas tubular function was monitored by 99mTc-DMSA scintigraphy, urine beta 2-microglobulin, urine N-acetyl glucosaminidase, and alanine aminopeptidase and a urine concentration test. In the patients given the highest irradiation dose to the entire left kidney, that is, 40 Gy in 5 1/2 weeks, glomerular and tubular functional impairment, as assessed scintigraphically, progressed at a rate of 2.0 +/- 1.0% (+/- 1 SD) and 2.0 +/- 0.5% per month, respectively, down to 30-40% after 3 to 5 years. The overall glomerular function, as assessed by creatinine clearance, decreased by only 20%. In the patients irradiated unilaterally on the upper pole to 40 Gy in 4 weeks, glomerular and tubular function in the left kidney deteriorated at 0.75 +/- 0.33% and 0.75 +/- 0.20% per month in the first 2 years, down to 75-80% at 5 years. This smaller reduction was due to shielding of a part of the left kidney. No changes were observed, thus far, after bilateral whole kidney irradiation to 17-18 Gy in 3 1/2 weeks. The concentration capacity of the kidney after total volume irradiation was not impaired. There was a trend for an increase in diastolic blood pressure in 3 out of 5 patients given the high dose irradiation to the entire left kidney and in 2 out of 7 patients irradiated on the upper pole of the left kidney. The progressive nature of the radiation nephropathy stresses the need for long term follow-up to determine more accurately the "tolerance dose" of the human kidney for irradiation.