A mathematical modelling tool for predicting survival of individual patients following resection of glioblastoma: a proof of principle

The prediction of the outcome of individual patients with glioblastoma would be of great significance for monitoring responses to therapy. We hypothesise that, although a large number of genetic-metabolic abnormalities occur upstream, there are two ‘final common pathways' dominating glioblastoma growth – net rates of proliferation (ρ) and dispersal (D). These rates can be estimated from features of pretreatment MR images and can be applied in a mathematical model to predict tumour growth, impact of extent of tumour resection and patient survival. Only the pre-operative gadolinium-enhanced T1-weighted (T1-Gd) and T2-weighted (T2) volume data from 70 patients with previously untreated glioblastoma were used to derive a ratio D/ρ for each patient. We developed a ‘virtual control' for each patient with the same size tumour at the time of diagnosis, the same ratio of net invasion to proliferation (D/ρ) and the same extent of resection. The median durations of survival and the shapes of the survival curves of actual and ‘virtual' patients subjected to biopsy or subtotal resection (STR) superimpose exactly. For those actually receiving gross total resection (GTR), as shown by post-operative CT, the actual survival curve lies between the ‘virtual' results predicted for 100 and 125% resection of the T1-Gd volume. The concordance between predicted (virtual) and actual survivals suggests that the mathematical model is realistic enough to allow precise definition of the effectiveness of individualised treatments and their site(s) of action on proliferation (ρ) and/or dispersal (D) of the tumour cells without knowledge of any other clinical or pathological information

Source localization of reaction-diffusion models for brain tumors

We propose a mathematically well-founded approach for locating the source (initial state) of density functions evolved within a nonlinear reaction-diffusion model. The reconstruction of the initial source is an ill-posed inverse problem since the solution is highly unstable with respect to measurement noise. To address this instability problem, we introduce a regularization procedure based on the nonlinear Landweber method for the stable determination of the source location. This amounts to solving a sequence of well-posed forward reaction-diffusion problems. The developed framework is general, and as a special instance we consider the problem of source localization of brain tumors. We show numerically that the source of the initial densities of tumor cells are reconstructed well on both imaging data consisting of simple and complex geometric structures

Male Eating Disorder Symptom Patterns and Health Correlates From 13 to 26 Years of Age

Objective: Research on the manifestations and health correlates of eating disorder symptoms among males is lacking. This study identified patterns of appearance concerns and eating disorder behaviors from adolescence through young adulthood and their health correlates. / Method: Participants were 7,067 males from the prospective Growing Up Today Study. Surveys from 1999 to 2007 (spanning ages 13−26 years) provided repeated measures data on muscularity and leanness concerns, eating disorder behaviors (purging, overeating, binge eating, use of muscle-building products), and health correlates (obesity, non-marijuana drug use, binge drinking, and depressive symptoms). / Results: Latent class analyses of observations at ages 13 to 15, 16 to 18, 19 to 22, and 23 to 26 years identified 1 large Asymptomatic class and 4 symptomatic patterns: Body Image Disturbance (high appearance concerns, low eating disorder behaviors; 1.0%−6.0% per age period); Binge Eating/Purging (binge eating and purging, use of muscle-building products, low appearance concerns; 0.1%−2.5%); Mostly Asymptomatic (low levels of muscularity concern, product use, and overeating; 3.5%−5.0%); and Muscularity Concerns (high muscularity concerns and use of products; 0.6%−1.0%). The Body Image Disturbance class was associated with high estimated prevalence of depressive symptoms. Males in the Binge Eating/Purging and Muscularity Concerns classes had high prevalence of binge drinking and drug use. Despite exhibiting modestly greater appearance concerns and eating disorder behaviors than the Asymptomatic class, being in the Mostly Asymptomatic class was prospectively associated with adverse health outcomes. / Conclusion: Results underscore the importance of measuring concerns about leanness, muscularity, and use of muscle-building products when assessing eating disorder presentations among males in research and clinical settings

Identification of plasma lipid biomarkers for prostate cancer by lipidomics and bioinformatics

Background: Lipids have critical functions in cellular energy storage, structure and signaling. Many individual lipid molecules have been associated with the evolution of prostate cancer; however, none of them has been approved to be used as a biomarker. The aim of this study is to identify lipid molecules from hundreds plasma apparent lipid species as biomarkers for diagnosis of prostate cancer. Methodology/Principal Findings: Using lipidomics, lipid profiling of 390 individual apparent lipid species was performed on 141 plasma samples from 105 patients with prostate cancer and 36 male controls. High throughput data generated from lipidomics were analyzed using bioinformatic and statistical methods. From 390 apparent lipid species, 35 species were demonstrated to have potential in differentiation of prostate cancer. Within the 35 species, 12 were identified as individual plasma lipid biomarkers for diagnosis of prostate cancer with a sensitivity above 80%, specificity above 50% and accuracy above 80%. Using top 15 of 35 potential biomarkers together increased predictive power dramatically in diagnosis of prostate cancer with a sensitivity of 93.6%, specificity of 90.1% and accuracy of 97.3%. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) demonstrated that patient and control populations were visually separated by identified lipid biomarkers. RandomForest and 10-fold cross validation analyses demonstrated that the identified lipid biomarkers were able to predict unknown populations accurately, and this was not influenced by patient's age and race. Three out of 13 lipid classes, phosphatidylethanolamine (PE), ether-linked phosphatidylethanolamine (ePE) and ether-linked phosphatidylcholine (ePC) could be considered as biomarkers in diagnosis of prostate cancer. Conclusions/Significance: Using lipidomics and bioinformatic and statistical methods, we have identified a few out of hundreds plasma apparent lipid molecular species as biomarkers for diagnosis of prostate cancer with a high sensitivity, specificity and accuracy

Animal-related factors associated with moderate-to-severe diarrhea in children younger than five years in western Kenya: A matched case-control study

Background Diarrheal disease remains among the leading causes of global mortality in children younger than 5 years. Exposure to domestic animals may be a risk factor for diarrheal disease. The objectives of this study were to identify animal-related exposures associated with cases of moderate-to-severe diarrhea (MSD) in children in rural western Kenya, and to identify the major zoonotic enteric pathogens present in domestic animals residing in the homesteads of case and control children. Methodology/Principal findings We characterized animal-related exposures in a subset of case and control children (n = 73 pairs matched on age, sex and location) with reported animal presence at home enrolled in the Global Enteric Multicenter Study in western Kenya, and analysed these for an association with MSD. We identified potentially zoonotic enteric pathogens in pooled fecal specimens collected from domestic animals resident at children’s homesteads. Variables that were associated with decreased risk of MSD were washing hands after animal contact (matched odds ratio [MOR] = 0.2; 95% CI 0.08–0.7), and presence of adult sheep that were not confined in a pen overnight (MOR = 0.1; 0.02–0.5). Variables that were associated with increased risk of MSD were increasing number of sheep owned (MOR = 1.2; 1.0–1.5), frequent observation of fresh rodent excreta (feces/urine) outside the house (MOR = 7.5; 1.5–37.2), and participation of the child in providing water to chickens (MOR = 3.8; 1.2–12.2). Of 691 pooled specimens collected from 2,174 domestic animals, 159 pools (23%) tested positive for one or more potentially zoonotic enteric pathogens (Campylobacter jejuni, C. coli, non-typhoidal Salmonella, diarrheagenic E. coli, Giardia, Cryptosporidium, or rotavirus). We did not find any association between the presence of particular pathogens in household animals, and MSD in children. Conclusions and significance Public health agencies should continue to promote frequent hand washing, including after animal contact, to reduce the risk of MSD. Future studies should address specific causal relations of MSD with sheep and chicken husbandry practices, and with the presence of rodents

Predicting the outcome of grade II glioma treated with temozolomide using proton magnetic resonance spectroscopy

International audienceBACKGROUND: This study was designed to evaluate proton magnetic resonance spectroscopy ((1)H-MRS) for monitoring the WHO grade II glioma (low-grade glioma (LGG)) treated with temozolomide (TMZ).METHODS: This prospective study included adult patients with progressive LGG that was confirmed by magnetic resonance imaging (MRI). Temozolomide was administered at every 28 days. Response to TMZ was evaluated by monthly MRI examinations that included MRI with volumetric calculations and (1)H-MRS for assessing Cho/Cr and Cho/NAA ratios. Univariate, multivariate and receiver-operating characteristic statistical analyses were performed on the results.RESULTS: A total of 21 LGGs from 31 patients were included in the study, and followed for at least n=14 months during treatment. A total of 18 (86%) patients experienced a decrease in tumour volume with a greater decrease of metabolic ratios. Subsequently, five (28%) of these tumours resumed growth despite the continuation of TMZ administration with an earlier increase of metabolic ratios of 2 months. Three (14%) patients did not show any volume or metabolic change. The evolutions of the metabolic ratios, mean(Cho/Cr)(n) and mean(Cho/NAA)(n), were significantly correlated over time (Spearman ρ=+0.95) and followed a logarithmic regression (P>0.001). The evolutions over time of metabolic ratios, mean(Cho/Cr)(n) and mean(Cho/NAA)(n), were significantly correlated with the evolution of the mean relative decrease of tumour volume, mean(ΔV(n)/V(o)), according to a linear regression (P<0.001) in the 'response/no relapse' patient group, and with the evolution of the mean tumour volume (meanV(n)), according to an exponential regression (P<0.001) in the 'response/relapse' patient group. The mean relative decrease of metabolic ratio, mean(Δ(Cho/Cr)(n)/(Cho/Cr)(o)), at n=3 months was predictive of tumour response over the 14 months of follow-up. The mean relative change between metabolic ratios, mean((Cho/NAA)(n)-(Cho/Cr)(n))/(Cho/NAA)(n), at n=4 months was predictive of tumour relapse with a significant cutoff of 0.046, a sensitivity of 60% and a specificity of 100% (P=0.004).CONCLUSIONS: The (1)H-MRS profile changes more widely and rapidly than tumour volume during the response and relapse phases, and represents an early predictive factor of outcome over 14 months of follow-up. Thus, (1)H-MRS may be a promising, non-invasive tool for predicting and monitoring the clinical response to TMZ