Childhood Nephroblastoma Research Articles

The relationship between vascular endothelial growth factor expression and the risk of childhood nephroblastoma: systematic review and meta-analysis.

BackgroundThis study explores the correlation between vascular endothelial growth factor expression and the risk of childhood nephroblastoma.MethodsPubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang database were searched to collect independent study data published in China between 2010 and 2021 on the expression and significance of VEGF in childhood nephroblastoma, and literature heterogeneity was tested. The odds ratio (OR) value was used as the effect indicator. Meta-analysis software RevMan 4.2.2 was used, and the original data of each study were statistically processed to calculate the combined OR value and 95% confidence interval (CI).ResultsTwelve studies involving 1,226 cases of pediatric nephroblastoma were included for systematic evaluation. The 12 randomized controlled studies reported the expression of VEGF in childhood nephroblastoma (OR =9.06, 95% CI: 6.97–11.78, P<0.00001). There was a statistically significant difference in expression of VEGF between the unfavorable histology (UH) group and the favorable histology (FH) group (OR =1.17, 95% CI: 1.07–1.27, P=0.0006) and expression of VEGF in different clinical stages of nephroblastoma, including stage I–II and III–IV (OR =0.49, 95% CI: 0.42–0.58, P<0.00001). Positive expression of VEGF showed no significant statistical difference between cases with and without tumor metastasis (OR =1.08, 95% CI: 0.86–1.36, P=0.50).ConclusionsThe expression of VEGF may play an important role in the occurrence and development of childhood nephroblastoma and could help guide clinicians to judge disease and treatment.

Fos-Related Antigen 1 May Cause Wnt-Fzd Signaling Pathway-Related Nephroblastoma in Children.

This study aimed to investigate the role of the primary Fos-related antigen 1 (Fosl-1) oncogene in nephroblastoma by studying 60 childhood nephroblastoma and 58 paraneoplastic carcinoma cases. The Fosl-1 expression was detected using immunohistochemistry. In vitro culture of nephroblastoma cells was performed by viral transfection to establish Fosl-1 overexpression and gene knockout models. Flow cytometry and nano-PCR were used to detect apoptosis and mRNA expression in related pathway genes. Immunohistochemical results showed that the positive expression of Fosl-1 in the nuclei of nephroblastoma tissue was 78%, among which metastasis rate was 61.7%; correspondingly, it was 8%, and 100% in adjacent tissues. The qPCR results indicated that MMP9, Wnt1, and Fzd1 were significantly upregulated after Fosl-1 overexpression compared with the normal embryonic tissue cells, control, and gene knockout groups (P <0.05). Fosl-1 could cause the occurrence, development, and metastasis of childhood nephroblastoma through wingless/int1/Frizzled-related signaling pathways.

Outcome of treatment of childhood nephroblastoma in a low middle income country: Ten-year experience in Sri Lanka

Outcome of treatment of childhood nephroblastoma in a low middle income country: Ten-year experience in Sri Lanka

Metabolic syndrome detection with biomarkers in childhood cancer survivors.

Purpose:Augmented survival of childhood nephroblastoma and neuroblastoma has increased long-term side effects such as metabolic syndrome (MetS). Risk stratification is difficult after abdominal radiation because waist circumference underestimates adiposity. We aimed to develop a strategy for determining MetS in irradiated survivors using an integrated biomarker profile and vascular ultrasonography.Methods:The NCEP-ATPIII MetS-components, 14 additional serum biomarkers and 9 vascular measurements were assessed in a single-centre cohort of childhood nephroblastoma (n = 67) and neuroblastoma (n = 36) survivors and controls (n = 61). Multivariable regression models were used to study treatment effects. Principal component analysis (PCA) was used to study all biomarkers in a combined analysis, to identify patterns and correlations.Results:After 27.5 years of follow-up, MetS occurred more often in survivors (14%) than controls (3%). Abdominal radiotherapy and nephrectomy, to a lesser extent, were associated with MetS and separate components and with several biomarker abnormalities. PCA of biomarkers revealed a pattern on PC1 from favourable lipid markers (HDL-cholesterol, adiponectin) towards unfavourable markers (triglycerides, LDL-cholesterol, apoB, uric acid). Abdominal radiotherapy was associated with the unfavourable biomarker profile (β = 1.45, P = 0.001). Vascular measurements were not of added diagnostic value.Conclusions:Long-term childhood nephro- and neuroblastoma survivors frequently develop MetS. Additional assessment of biomarkers identified in PCA – adiponectin, LDL, apoB, and uric acid – may be used especially in abdominally irradiated survivors, to classify MetS as alternative for waist circumference. Vascular ultrasonography was not of added value.

Childhood nephroblastoma in Southern and Eastern Europe and the US: Incidence variations and temporal trends by human development index

BackgroundDespite advances in the management of nephroblastoma (Wilms’ tumor, WT), the etiology of the tumor remains obscure. We aimed to compare nephroblastoma incidence rates and time trends among children (0–14 years) in 12 Southern and Eastern European (SEE) countries and the Surveillance, Epidemiology, and End Results Program (SEER), USA, in relation to the human development index (HDI). MethodsIn total 1776 WT cases were recorded in 13 SEE collaborating registries (circa 1990–2016), whereas data on 2260 cases (1990–2012) were extracted from the SEER database. Age-standardized incidence rates (AIRs) were calculated and correlated with HDI, whereas temporal trends were evaluated using Poisson regression and Joinpoint analyses. ResultsThe overall SEE AIR (9.2/106) was marginally higher than that of the SEER (8.3/106), whereas significant differences were noted among the 13 SEE registries which comprised mainly Caucasian populations. A statistically significant temporal increase in incidence was noted only in Belarus. Most cases (∼75%) were diagnosed before the fifth year of life, with rates steadily declining thereafter; median age at diagnosis was similar in SEE countries and SEER. A slight male preponderance in the first year of life (male:female = 1.1) was followed by a female preponderance in the older age groups (male:female = 0.7). Lastly, a statistically significant positive association between higher HDI and increasing nephroblastoma incidence was noted (regression coefficient: +3.25, 95%CI: +1.35, +5.15). ConclusionsVariations in incidence and time trends across the examined registries, changing male-to-female patterns with advancement in age, and positive associations with the HDI imply a plausible role for environmental and genetic factors in disease etiology, and these need to be explored further.

Autophagy Inhibition in Childhood Nephroblastoma and the Therapeutic Significance.

Autophagy is a physiological pathway characterized by lysosomedependent self-digestion to recycle damaged or superfluous cellular content. Deregulation of autophagy hampers the maintenance of cellular homeostasis and contributes to tumorigenesis. However, during anticancer therapy, autophagy activation contributes to development of resistance. Thus autophagy has been recognized as an important pathway and a therapeutic target in cancer. Nephroblastoma (Wilm's tumor) is a common childhood malignancy. The role of autophagy in nephroblastoma is largely uninvestigated. This study is to investigate the change of autophagy level in nephroblastoma, and whether autophagy could be a therapeutic target in anaplastic nephroblastoma. In clinical samples of childhood nephroblastoma, autophagy activity was evaluated by the expressions of selected autophagy markers as well as the presence of autophagosome ultrastructure. Use of autophagy inhibitors alone and in combination with conventional chemotherapeutics, was studied both in vivo and in vitro. In nephroblastoma, there was decrease in the Beclin 1 level and the number of autophagosomes, suggesting autophagy inhibition. Furthermore, in two anaplastic nephroblastoma cell lines, G401 and SK-NEP1, autophagy inhibitors further enhanced the efficacy of conventional chemotherapeutics including vincristine and cisplatin. In G401 tumor model established in nude mice, combinational use of chloroquine, an inhibitor of autophagy degradation, further decreased the tumor mass compared with single use of the chemotherapeutics vindesine, although no statistical significance was achieved. Our results suggest that autophagy deregulation is involved in nephroblastoma, and targeting autophagy can serve as a potential adjuvant strategy for the highly malignant cases.

Childhood Wilm\'s tumour: prognostic factors in north central Nigeria

Childhood Wilms' tumour or nephroblastoma represents one of the challenges for paediatric oncologists in developing countries. To review the clinical characteristics and outcome of management of childhood nephroblastoma in North- Central Nigeria. The clinical, operative and histological records of children aged 15 years and below, that were managed for Wilms' tumour at the Jos University Teaching Hospital between 1998 and 2005 were retrospectively reviewed. There were 32 children (M:F=1.9:1) with histologically confirmed nephroblastoma seen over the 7-year period. Their median(range) age was 4 (3-15) years. The patients invariably presented with a palpable abdominal mass, but haematuria was exceptional. The neoplasm tended to be larger on average than those reported previously among Caucasian children. At presentation, 1 (3.1%) patient was in stage I, 8 (25%) stage II, 11 (34.4%) stage III and 12 (37.5%) stage IV. About 72% of the patients presented with stage III-IV disease. Poorly differentiated neoplasm was more common in male than in female patients. Nephrectomy and chemotherapy were the modality of treatment. Fifteen (46.9%) of the patients received little or no induction chemotherapy due to unavailability of drugs while only 12 (37.5%) received the prescribed maintenance treatment with the remainder getting erratic or no treatment. Overall, only 43.8% were alive between 1 and 9 months (median: 6 months) of follow-up period, but there was no survivor at two years after treatment. Childhood nephroblastoma has a high mortality rate in north central Nigeria because of late clinical presentation with advanced disease, poor availability of cytotoxic drugs and frequent interruptions in treatment and inadequate follow-up.

POWER AND SAMPLE SIZE DETERMINATION FOR NONINFERIORITY TRIALS USING AN EXACT METHOD

Noninferiority studies are frequently conducted to justify the development of new drugs and vaccines that have been shown to offer better safety profiles, easier administration, or lower cost while maintaining similar efficacy as compared to the standard treatment. Recently, exact methods have been developed to address the concern that existing asymptotic methods for analyzing and planning noninferiority may fail because of small sample size or because of skewed or sparse data structure. In this paper, we explore the use of exact methods in determining sample size and power for noninferiority studies that focus on the difference of two proportions. The methodology for sample size and power calculations is developed based on an exact unconditional test of noninferiority. We illustrate this exact method using a clinical trial example in childhood nephroblastoma and briefly discuss the optimal sample-size allocation strategy. This exact unconditional method performs very well in various scenarios and compares favorably to its asymptotic counterpart in terms of sensitivity. Therefore, it is a very desirable tool for planning noninferiority trials, especially in situations where asymptotic methods are likely to fail.

TUMORIGENICITY ASSOCIATED WITH CHROMOSOME 11P15 ALTERATIONS IN SV40-TRANSFORMED HUMAN KIDNEY-CELLS

Chromosome 11p15 has been suggested to be a potential site for a second Wilms' tumour gene (a childhood nephroblastoma). Human foetal kidney cells and normal kidney cells from Wilms' tumour patients were transformed with SV40 derivative vectors. As some of the cell lines progressed to tumorigenicity, we observed that chromosome 11p13, site of the WT1 suppressor gene, did not show any allelic loss. However, RFLP analysis showed that chromosome 11p15 was affected by allelic losses on different genes in some cell lines but not necessarily prior to the appearance of tumorigenicity. We also observed that the most aggressive cell Line (SVCU/NK), derived from the normal kidney cells of a Wilms' tumour patient, showed increased expression of c-Ha-ras proto-oncogene at later passage and in the tumour tissue extracted from nude mice. Finally we report a lack of tumour suppression activity of one cell line SVT1B6/NK, when fused with the tumorigenic G401 cell line (the latter has been used in tumour suppression experiments as a Wilms' tumour cell line before being identified as a Rhabdoid tumour cell line). These experiments are consistent with the existence of a suppressor gene at chromosome 11p15.

Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping

Cytogenetic analysis has identified chromosome 11p13 as the smallest overlap region for deletions found in individuals with WAGR syndrome, which includes Wilms tumour (a recessive childhood nephroblastoma), aniridia, genito-urinary abnormalities and mental retardation. The underlying loci have since been resolved into an aniridia (AN2) locus at a telomeric position, and a locus of closely spaced genes or a single pleiotropic gene involved in genito-urinary tract abnormalities and Wilms tumour at a more centromeric position. Pulsed-field gel analysis of the 11p13 region has revealed the presence of several putative CpG islands, structures which are frequently associated with the 5' ends of expressed sequences, mainly housekeeping genes and some tissue-specific genes. Starting from a CpG island, we have now isolated four neighbouring CpG islands, all within 650 kilobases (kb), by means of two consecutive bidirectional jumps in rare-cutting restriction-enzyme jumping libraries. In two instances, flanking sequences were conserved in other species and RNA transcripts were identified. A complementary DNA clone isolated for one of them derives from an RNA highly expressed in fetal kidney, and is predicted to encode a Krüppel-like zinc-finger protein that is probably a transcription factor. The entire cDNA region is included in two partially overlapping homozygous deletions found in Wilms tumour DNA samples. Cloning of the breakpoints in one tumour revealed a deletion size of 170 kb, one-third of which is covered by the cDNA. The expression pattern and sequence of this cDNA could point to an important role for its corresponding gene in the normal development of the renal system as well as in Wilms tumour.

How to establish equivalence between treatments: A one‐sided clinical trial in paediatric oncology

The design of clinical trial to establish the equivalence of two treatments differs from that of an efficacy trial. The conventional null hypothesis of equivalent treatment efficacy is replaced by a null hypothesis of inequivalence which must be tested by appropriate statistics. In addition, the maximum allowable value of the true difference between the efficacy of two equivalent treatments must be specified. In oncology, such a trial is necessary when a standard treatment is replaced by a new less toxic one of equivalent efficacy. The statistical formulation is one-sided. A trial comparing two pre-operative treatments in childhood nephroblastoma is presented here and analysed according to this methodology.

Adult nephroblastoma — Five cases treated by surgery, radiotherapy and chemotherapy

Nephroblastoma in adults is rare; consequently very little experience of treatment for adult cases has been reported. We report five cases of adult nephroblastoma managed by nephrectomy, radiotherapy and combination chemotherapy. The treatment schedules were derived from childhood nephroblastoma regimens. However, four of the five patients were dead within 12 months of nephrectomy and all five had progression of disease whilst on combination chemotherapy. A good prognosis should not be anticipated for adult nephroblastoma. The chemotherapy schedules which are so successful in childhood nephroblastoma may require modification to improve prognosis in adults.