Search

Abstract: Background: Quantitative real-time (q)PCR for detection of minimal residual disease (MRD) in children with neuroblastoma (NB) can evaluate molecular bone marrow (BM) response to therapy, but the prognostic value of tumour kinetics in the BM during induction treatment remains to be established. The purpose of this study was to analyse at which time points MRD detection by sequential molecular assessment of BM was prognostic for overall survival (OS). Methods: In this single centre study, qPCR was performed with five NB-specific markers: PHOX2B, TH, DDC, GAP43 and CHRNA3, on 106 retrospectively analysed BM samples of 53 patients >1year with stage 4 neuroblastoma. The prognostic impact of MRD at diagnosis (n =39), at 3months after diagnosis (n =38) and after completing induction chemotherapy (n =29) was assessed using univariate and bivariate Cox regression analyses. Results: There was no correlation between tumour load at diagnosis and outcome (p =0.93). Molecular BM remission was observed in 11/38 (29%) of patients at 3months after diagnosis and associated with favourable outcome (5-y-OS 62±15.0% versus 19±8%; p =0.009). After completion of induction chemotherapy, BM of 41% (12/29) of the patients was still MRD positive, which was associated with poor outcome (5-y-OS 0% versus 52±12%; p <0.001). For both time points, the prognostic value of molecular response remained significant in bivariate analysis. Conclusions: MRD detection measured by a panel of NB specific-PCR targets could identify fast responders, who clear their BM early during treatment. Fast molecular response was a prognostic factor, associated with better outcome. Our data indicate that MRD analysis during induction therapy should be included in prospective MRD studies. [Copyright &y& Elsevier]

Abstract: Sediment and groundwater profiles were compared in two villages of Bangladesh to understand the geochemical and hydrogeological factors that regulate dissolved As concentrations in groundwater. In both villages, fine-grained sediment layers separate shallow aquifers (< 28 m) high in As from deeper aquifers (40–90 m) containing < 10 μg/L As. In one village (Dari), radiocarbon dating indicates deposition of the deeper aquifer sediments > 50 ka ago and a groundwater age of thousands of years. In the other village (Bay), the sediment is < 20 ka old down to 90 m and the deeper aquifer groundwater is younger, on the order of hundreds of years. The shallow aquifers in both villages that are high in As contain bomb-3H and bomb-14C, indicating recent recharge. The major and minor ion compositions of the shallow and deeper aquifers also differ significantly. Deeper aquifer water is of the Na+-HCO3 – type, with relatively little dissolved NH4 + (76 ± 192 μmol/L), Fe (27 ± 43 μmol/L) and Mn (3 ± 2 μmol/L). In contrast, shallow aquifer water is of the Ca2+-Mg2+-HCO3 – type, with elevated concentrations of dissolved NH4 + (306 ± 355 μmol/L), Fe (191 ± 73 μmol/L), and Mn (27 ± 43 μmol/L). In both villages, the quantity of As extractable from deeper aquifer sands with a 1 mol/L phosphate solution (0.2 ± 0.3 mg/kg, n = 12; 0.1 ± 0.1 mg/kg, n = 5) is 1 order of magnitude lower than P-extractable As from shallow deposits (1.7 ± 1.2 mg/kg, n = 9; 1.4 ± 2.0 mg/kg, n = 11). The differences suggest that the concentration of P-extractable As in the sediment is a factor controlling the concentration of As in groundwater. Low P-extractable As levels are observed in both deeper aquifers that are low in As, even though there is a large difference in the time of deposition of these aquifers in the two villages. The geochemical data and hydrographs presented in this study suggest that both Holocene and Pleistocene deeper aquifers that are low in As should be a viable source of drinking water as long as withdrawals do not exceed recharge rates of ∼1 cm/yr. [Copyright &y& Elsevier]

Loss of heterozygosity (LOH) of the distal part of the short arm of chromosome 1 in neuroblastoma is a well characterised phenomenon. In addition, previous reports have described interstitial deletions outside the common region of loss on chromosome 1p36, suggesting additional tumour suppressor loci. In this study, we have searched extensively for interstitial 1p deletions in a panel of 67 neuroblastoma samples from clinically-detected cases. We used three VNTR probes and 10 dinucleotide markers from the 1p32-36 regions reported to show interstitial deletions. Fifteen (22%) tumours showed telomeric LOH without evidence for more proximal interstitial deletions. Forty-five tumours showed no LOH or allelic imbalance. Seven (10%) tumours demonstrated allelic imbalance for one or more markers. These tumours were subsequently analysed by fluorescent in situ hybridisation (FISH) and flow cytometry. The patterns found in all seven tumours were consistent with copy number changes of the entire chromosome 1, without evidence for interstitial deletions. This study indicates that interstitial deletions of chromosome 1p are rare in clinically-detected neuroblastoma when analysed by a combination of molecular and cytogenetic techniques. [Copyright &y& Elsevier]