Folate pathway gene polymorphisms and risk of childhood brain tumors: Results from an Australian case-control study

Background: Recent research suggests that maternal folic acid supplementation is associated with a reduced risk of childhood brain tumors (CBT); polymorphisms in folate pathway genes could modify this association or directly influence CBT risk. Methods: Associations between risk of CBT and folate pathway polymorphisms were investigated in a population-based case- control study in Australia (2005-2010). Cases were recruited through all Australian pediatric oncology centers and controls by national random digit dialing. Data were available from 321 cases and 552 controls. Six polymorphisms were genotyped in children and parents (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756A>G, MTR 5049C>A, and CBS 2199 T>C). Maternal folic acid use was ascertained via questionnaire. ORs were estimated using unconditional logistic regression. Case-parent trio analyses were also undertaken. Results: There was weak evidence of a reduced risk of CBT for the MTRR 66GG genotype in the child or father: ORs 0.71 [95% confidence interval (CI), 0.48-1.07]; 0.54 (95% CI, 0.34-0.87), respectively. Maternal prepregnancy folic acid supplementation showed a stronger negative association with CBT risk where the child, mother, or father had the MTRR 66GG genotype (Pinteraction = 0.07, 0.10, and 0.18, respectively). Conclusions: Evidence for an association between folate pathway genotypes and CBT is limited in this study. There was possible protection by the MTRR 66GG genotype, particularly when combined with maternal prepregnancy folic acid supplementation; these results are novel and require replication. Impact: The possible interaction between folic acid supplementation and MTRR 66A>G, if confirmed, would strengthen evidence for prepregnancy folate protection against CBT

Confirmation of childhood acute lymphoblastic leukemia variants, ARID5B and IKZF1, and interaction with parental environmental exposures.

Genome wide association studies (GWAS) have established association of ARID5B and IKZF1 variants with childhood acute lymphoblastic leukemia (ALL). Epidemiological studies suggest that environmental factors alone appear to make a relatively minor contribution to disease risk. The polygenic nature of childhood ALL predisposition together with the timing of environmental triggers may hold vital clues for disease etiology. This study presents results from an Australian GWAS of childhood ALL cases (n = 358) and population controls (n = 1192). Furthermore, we utilised family trio (n = 204) genotypes to extend our investigation to gene-environment interaction of significant loci with parental exposures before conception, and child's sex and age. Thirteen SNPs achieved genome wide significance in the population based case/control analysis; ten annotated to ARID5B and three to IKZF1. The most significant SNPs in these regions were ARID5B rs4245595 (OR 1.63, CI 1.38-1.93, P = 2.13×10(-9)), and IKZF1 rs1110701 (OR 1.69, CI 1.42-2.02, p = 7.26×10(-9)). There was evidence of gene-environment interaction for risk genotype at IKZF1, whereby an apparently stronger genetic effect was observed if the mother took folic acid or if the father did not smoke prior to pregnancy (respective interaction P-values: 0.04, 0.05). There were no interactions of risk genotypes with age or sex (P-values >0.2). Our results evidence that interaction of genetic variants and environmental exposures may further alter risk of childhood ALL however, investigation in a larger population is required. If interaction of folic acid supplementation and IKZF1 variants holds, it may be useful to quantify folate levels prior to initiating use of folic acid supplements

Household vacuum cleaners vs. the high-volume surface sampler for collection of carpet dust samples in epidemiologic studies of children

<p>Abstract</p> <p>Background</p> <p>Levels of pesticides and other compounds in carpet dust can be useful indicators of exposure in epidemiologic studies, particularly for young children who are in frequent contact with carpets. The high-volume surface sampler (HVS3) is often used to collect dust samples in the room in which the child had spent the most time. This method can be expensive and cumbersome, and it has been suggested that an easier method would be to remove dust that had already been collected with the household vacuum cleaner. However, the household vacuum integrates exposures over multiple rooms, some of which are not relevant to the child's exposure, and differences in vacuuming equipment and practices could affect the chemical concentration data. Here, we compare levels of pesticides and other compounds in dust from household vacuums to that collected using the HVS3.</p> <p>Methods</p> <p>Both methods were used in 45 homes in California. HVS3 samples were collected in one room, while the household vacuum had typically been used throughout the home. The samples were analyzed for 64 organic compounds, including pesticides, polycyclic aromatic hydrocarbons, and polychlorinated biphenyls (PCBs), using GC/MS in multiple ion monitoring mode; and for nine metals using conventional microwave-assisted acid digestion combined with ICP/MS.</p> <p>Results</p> <p>The methods agreed in detecting the presence of the compounds 77% to 100% of the time (median 95%). For compounds with less than 100% agreement, neither method was consistently more sensitive than the other. Median concentrations were similar for most analytes, and Spearman correlation coefficients were 0.60 or higher except for allethrin (0.15) and malathion (0.24), which were detected infrequently, and benzo(k)fluoranthene (0.55), benzo(a)pyrene (0.55), PCB 105 (0.54), PCB 118 (0.54), and PCB 138 (0.58). Assuming that the HVS3 method is the "gold standard," the extent to which the household vacuum cleaner method yields relative risk estimates closer to unity by increasing random measurement error varies by compound and depends on the method used to calculate relative risk.</p> <p>Conclusion</p> <p>The household vacuum cleaner method appears to be a reasonable alternative to the HVS3 for detecting, ranking, and quantifying the concentrations of pesticides and other compounds in carpet dust.</p

Asbestos-related pleural and lung fibrosis in patients with retroperitoneal fibrosis

<p>Abstract</p> <p>Background</p> <p>Retroperitoneal fibrosis (RPF) is a rare fibroinflammatory disease that leads to hydronephrosis and renal failure. In a case-control study, we have recently shown that asbestos exposure was the most important risk factor for RPF in the Finnish population. The aim of this study was to evaluate the relation of asbestos exposure to radiologically confirmed lung and pleural fibrosis among patients with RPF.</p> <p>Methods</p> <p>Chest high-resolution computed tomography (HRCT) was performed on 16 unexposed and 22 asbestos-exposed RPF patients and 18 asbestos-exposed controls. Parietal pleural plaques (PPP), diffuse pleural thickening (DPT) and parenchymal fibrosis were scored separately.</p> <p>Results</p> <p>Most of the asbestos-exposed RPF patients and half of the asbestos-exposed controls had bilateral PPP, but only a few had lung fibrosis. Minor bilateral plaques were detected in two of the unexposed RPF patients, and none had lung fibrosis. DPT was most frequent and thickest in the asbestos-exposed RPF-patients. In three asbestos-exposed patients with RPF we observed exceptionally large pleural masses that were located anteriorly in the pleural space and continued into the anterior mediastinum.</p> <p>Asbestos exposure was associated with DPT in comparisons between RPF patients and controls (case-control analysis) as well as among RPF patients (case-case analysis).</p> <p>Conclusion</p> <p>The most distinctive feature of the asbestos-exposed RPF patients was a thick DPT. An asbestos-related pleural finding was common in the asbestos-exposed RPF patients, but only a few of these patients had parenchymal lung fibrosis. RPF without asbestos exposure was not associated with pleural or lung fibrosis. The findings suggest a shared etiology for RPF and pleural fibrosis and furthermore possibly a similar pathogenetic mechanisms.</p

A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma

Our previous phase II study of cisplatin and gemcitabine in malignant mesothelioma showed a 47.6% (95% CI 26.2–69.0%) response rate with symptom improvement in responding patients. Here we confirm these findings in a multicentre setting, and assess the effect of this treatment on quality of life and pulmonary function. Fifty-three patients with pleural malignant mesothelioma received cisplatin 100 mg m−2 i.v. day 1 and gemcitabine 1000 mg m−2 i.v. days 1, 8, and 15 of a 28 day cycle for a maximum of six cycles. Quality of life and pulmonary function were assessed at each cycle. The best response achieved in 52 assessable patients was: partial response, 17 (33%, 95% CI 20–46%); stable disease, 31 (60%); and progressive disease, four (8%). The median time to disease progression was 6.4 months, median survival from start of treatment 11.2 months, and median survival from diagnosis 17.3 months. Vital capacity and global quality of life remained stable in all patients and improved significantly in responding patients. Major toxicities were haematological, limiting the mean relative dose intensity of gemcitabine to 75%. This schedule of cisplatin and gemcitabine is active in malignant mesothelioma in a multicentre setting. Investigation of alternative scheduling is needed to decrease haematological toxicity and increase the relative dose intensity of gemcitabine whilst maintaining response rate and quality of life

Vitamin A and Retinoid Derivatives for Lung Cancer: A Systematic Review and Meta Analysis

Despite reported antiproliferative activity of vitamin A and its common use for cancer, there is no comprehensive synthesis of its safety and efficacy in lung cancers. To address this issue we conducted a systematic review of the safety and efficacy of vitamin A for the treatment and prevention of lung cancers.Two independent reviewers searched six electronic databases from inception to July 2009 for clinical, observational, and preclinical evidence pertaining to the safety and efficacy of vitamin A and related retinoids for lung cancers. 248 studies were included for full review and analysis. Five RCTs assessed treatment of lung cancers, three assessed primary prevention, and three looked at secondary prevention of lung cancers. Five surrogate studies, 26 phase I/II, 32 observational, and 67 preclinical studies were also included. 107 studies were included for interactions between vitamin A and chemo- or radiation-therapy. Although some studies demonstrated benefits, there was insufficient evidence overall to support the use of vitamin A or related retinoids for the treatment or prevention of lung cancers. Retinyl palmitate combined with beta carotene increased risk of lung cancer in smokers in the large CARET trial. Pooling of three studies pertaining to treatment and three studies on secondary prevention revealed no significant effects on response rate, second primary tumor, recurrence, 5-year survival, and mortality. There was a small improvement in event free survival associated with vitamin A compared to controls, RR 1.24 (95% CI 1.13-1.35). The synthetic rexinoid bexarotene increased survival significantly among a subset of patients in two RCTs (p<0.014, <0.087).There is a lack of evidence to support the use of naturally occurring retinoids for the treatment and prevention of lung cancers. The rexinoid bexarotene may hold promise for use among a subset of patients, and deserves further study