Age-Related Differences in Susceptibility to Carcinogenesis: A Quantitative Analysis of Empirical Animal Bioassay Data

In revising cancer risk assessment guidelines, the U.S. Environmental Protection Agency (EPA) analyzed animal cancer bioassay data over different periods of life. In this article, we report an improved analysis of these data (supplemented with some chemical carcinogenesis observations not included in the U.S. EPA’s original analysis) and animal bioassay studies of ionizing radiation. We use likelihood methods to avoid excluding cases where no tumors were observed in specific groups. We express dosage for animals of different weights on a metabolically consistent basis (concentration in air or food, or per unit body weight to the three-quarters power). Finally, we use a system of dummy variables to represent exposures during fetal, preweaning, and weaning–60-day postnatal periods, yielding separate estimates of relative sensitivity per day of dosing in these intervals. Central estimate results indicate a 5- to 60-fold increased carcinogenic sensitivity in the birth–weaning period per dose ÷ (body weight(0.75)-day) for mutagenic carcinogens and a somewhat smaller increase—centered about 5-fold—for radiation carcinogenesis per gray. Effects were greater in males than in females. We found a similar increased sensitivity in the fetal period for direct-acting nitrosoureas, but no such increased fetal sensitivity was detected for carcinogens requiring metabolic activation. For the birth–weaning period, we found an increased sensitivity for direct administration to the pups similar to that found for indirect exposure via lactation. Radiation experiments indicated that carcinogenic sensitivity is not constant through the “adult” period, but the dosage delivered in 12- to 21-month-old animals appears a few-fold less effective than the comparable dosage delivered in young adults (90–105 days of age)

Children grow and horses race: is the adiposity rebound a critical period for later obesity?

BACKGROUND: The adiposity rebound is the second rise in body mass index that occurs between 3 and 7 years. An early age at adiposity rebound is known to be a risk factor for later obesity. The aim here is to clarify the connection between the age at rebound and the corresponding pattern of body mass index change, in centile terms, so as to better understand its ability to predict later fatness. DISCUSSION: Longitudinal changes in body mass index during adiposity rebound, measured both in original (kg/m(2)) and standard deviation (SD) score units, are studied in five hypothetical subjects. Two aspects of the body mass index curve, the body mass index centile and the rate of body mass index centile crossing, determine a child's age at rebound. A high centile and upward centile crossing are both associated separately with an early rebound, while a low centile and/or downward centile crossing correspond to a late rebound. Early adiposity rebound is a risk factor for later fatness because it identifies children whose body mass index centile is high and/or crossing upwards. Such children are likely to have a raised body mass index later in childhood and adulthood. This is an example of Peto's "horse racing effect". The association of centile crossing with later obesity is statistical not physiological, and it applies at all ages not just at rebound, so adiposity rebound cannot be considered a critical period for future obesity. Body mass index centile crossing is a more direct indicator of the underlying drive to fatness. SUMMARY: An early age at adiposity rebound predicts later fatness because it identifies children whose body mass index centile is high and/or crossing upwards. Such children are likely to have a raised body mass index later. Body mass index centile crossing is more direct than the timing of adiposity rebound for predicting later fatness

Novel statistical approaches for non-normal censored immunological data: analysis of cytokine and gene expression data

Background: For several immune-mediated diseases, immunological analysis will become more complex in the future with datasets in which cytokine and gene expression data play a major role. These data have certain characteristics that require sophisticated statistical analysis such as strategies for non-normal distribution and censoring. Additionally, complex and multiple immunological relationships need to be adjusted for potential confounding and interaction effects. Objective: We aimed to introduce and apply different methods for statistical analysis of non-normal censored cytokine and gene expression data. Furthermore, we assessed the performance and accuracy of a novel regression approach in order to allow adjusting for covariates and potential confounding. Methods: For non-normally distributed censored data traditional means such as the Kaplan-Meier method or the generalized Wilcoxon test are described. In order to adjust for covariates the novel approach named Tobit regression on ranks was introduced. Its performance and accuracy for analysis of non-normal censored cytokine/gene expression data was evaluated by a simulation study and a statistical experiment applying permutation and bootstrapping. Results: If adjustment for covariates is not necessary traditional statistical methods are adequate for non-normal censored data. Comparable with these and appropriate if additional adjustment is required, Tobit regression on ranks is a valid method. Its power, type-I error rate and accuracy were comparable to the classical Tobit regression. Conclusion: Non-normally distributed censored immunological data require appropriate statistical methods. Tobit regression on ranks meets these requirements and can be used for adjustment for covariates and potential confounding in large and complex immunological datasets

Breast cancer and childhood anthropometry: emerging hypotheses?

In this issue of Breast Cancer Research, Baer and colleagues report a strong protective effect of childhood and adolescent body fatness on premenopausal breast cancer risk based on a large prospective study. Methodological issues are discussed, as are tentative biological interpretations regarding the findings

Reconciling the potentially irreconcilable? Genotypic and phenotypic amoxicillin-clavulanate resistance in Escherichia coli

Resistance to amoxicillin-clavulanate, a widely used beta-lactam/beta-lactamase inhibitor combination antibiotic, is rising globally, and yet susceptibility testing remains challenging. To test whether whole-genome sequencing (WGS) could provide a more reliable assessment of susceptibility than traditional methods, we predicted resistance from WGS for 976 Escherichia coli bloodstream infection isolates from Oxfordshire, United Kingdom, comparing against phenotypes from the BD Phoenix (calibrated against EUCAST guidelines). A total of 339/976 (35%) isolates were amoxicillin-clavulanate resistant. Predictions based solely on beta-lactamase presence/absence performed poorly (sensitivity, 23% [78/339]) but improved when genetic features associated with penicillinase hyperproduction (e.g., promoter mutations and copy number estimates) were considered (sensitivity, 82% [277/339]; P < 0.0001). Most discrepancies occurred in isolates with MICs within ±1 doubling dilution of the breakpoint. We investigated two potential causes: the phenotypic reference and the binary resistant/susceptible classification. We performed reference standard, replicated phenotyping in a random stratified subsample of 261/976 (27%) isolates using agar dilution, following both EUCAST and CLSI guidelines, which use different clavulanate concentrations. As well as disagreeing with each other, neither agar dilution phenotype aligned perfectly with genetic features. A random-effects model investigating associations between genetic features and MICs showed that some genetic features had small, variable and additive effects, resulting in variable resistance classification. Using model fixed-effects to predict MICs for the non-agar dilution isolates, predicted MICs were in essential agreement (±1 doubling dilution) with observed (BD Phoenix) MICs for 691/715 (97%) isolates. This suggests amoxicillin-clavulanate resistance in E. coli is quantitative, rather than qualitative, explaining the poorly reproducible binary (resistant/susceptible) phenotypes and suboptimal concordance between different phenotypic methods and with WGS-based predictions

Randomized trial to compare the efficacy and toxicity of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with methotrexate mitoxantrone (MM) in advanced carcinoma of the breast

One hundred and sixteen patients with locally advanced or metastatic breast cancer were randomized to receive CMF (cyclophosphamide 600 mg m−2 day 1 and 8 i.v., 5-fluorouracil 600 mg m−2 day 1 and 8 i.v.,, methotrexate 40 mg m−2 day 1 and 8 i.v., monthly for 6 cycles) or MM (methotrexate 30 mg m−2, mitoxantrone 6.5 mg m−2, both i.v. day 1 3-weekly for 8 cycles) as first line treatment with chemotherapy. Objective responses occurred in 17 patients out of 58 (29%) who received CMF and nine out of 58 (15%) who received MM; 95% confidence interval for difference in response rates (–1%–29%), P = 0.07. No statistically significant differences were seen in overall survival or time to progression between the two regimes although a tendency towards a shorter progression time on the MM regime must be acknowledged. There was, however, significantly reduced haematological toxicity (P < 0.001) and alopecia (P < 0.001) and fewer dose reductions and delays in patients randomized to MM. No statistically significant differences were seen between the two regimes in terms of quality of life (QOL). However, some association between QOL and toxicity was apparent overall with pooled QOL estimates tending to indicate a worsening in psychological state with increasing maximum toxicity over treatment. Despite the fact that results surrounding response rates and time to progression did not reach statistical significance, their possible compatibility with an improved outcome on CMF treatment must be borne in mind. However, MM is a well-tolerated regimen with fewer side-effects than CMF, which with careful patient management and follow-up, therefore, may merit consideration as a first-line treatment to palliate patients with metastatic breast cancer who are infirm or elderly. © 1999 Cancer Research Campaig

Pathological complete response and residual DCIS following neoadjuvant chemotherapy for breast carcinoma

Patients who have no residual invasive cancer following neoadjuvant chemotherapy for breast carcinoma have a better overall survival than those with residual disease. Many classification systems assessing pathological response to neoadjuvant chemotherapy include residual ductal carcinoma in situ (DCIS) only in the definition of pathological complete response. The purpose of this study was to investigate whether patients with residual DCIS only have the same prognosis as those with no residual invasive or in situ disease. A retrospective analysis of a prospectively maintained database identified 435 patients, who received neoadjuvant chemotherapy for operable breast cancer between February 1985 and February 2003. Of these, 30 (7%; 95% CI 5–9%) had no residual invasive disease or DCIS and 20 (5%; CI 3–7%) had residual DCIS only. With a median follow-up of 61 months, there was no statistical difference in disease-free survival, 80% (95% CI 60–90%) in those with no residual invasive or in situ disease and 61% (95% CI 35–80%) in those with DCIS only (P=0.4). No significant difference in 5-year overall survival was observed, 93% (95% CI 75–98%) in those with no residual invasive or in situ disease and 82% (95% CI 52–94%) in those with DCIS only (P=0.3). Due to the small number of patients and limited number of events in each group, it is not possible to draw definitive conclusions from this study. Further analyses of other databases are required to confirm our finding of no difference in disease-free and overall survival between patients with residual DCIS and those with no invasive or in situ disease following neoadjuvant chemotherapy for breast cancer

Oestrogen receptor status, pathological complete response and prognosis in patients receiving neoadjuvant chemotherapy for early breast cancer

The aim of this study was to ascertain if oestrogen receptor ( ER) status predicts for pathological complete response (pCR) to neoadjuvant chemotherapy in operable breast cancer, and the effects of pCR on survival. Using a single-institution database, 435 patients were identified, who received neoadjuvant chemotherapy for operable breast cancer and were eligible for the analysis. Patients whose tumours were ER negative were more likely to achieve a pCR than patients who were ER positive (21.6 vs 8.1%,

Retinal thickness as potential biomarker in posterior cortical atrophy and typical Alzheimer's disease

BACKGROUND: Retinal thickness can be measured non-invasively with optical coherence tomography (OCT) and may offer compelling potential as a biomarker for Alzheimer's disease (AD). Retinal thinning is hypothesized to be a result of retrograde atrophy and/or parallel neurodegenerative processes. Changes in the visual pathway are of particular interest in posterior cortical atrophy (PCA), the most common atypical AD phenotype predominantly affecting the parietal-occipital cortices. We therefore evaluated retinal thickness as non-invasive biomarker of neurodegeneration in well-characterized participants with posterior cortical atrophy (PCA) and typical Alzheimer's disease (tAD). // METHODS: Retinal thickness measures were acquired from 48 patient participants (N = 25 PCA; N = 23 tAD) fulfilling consensus diagnostic criteria and 70 age-matched controls. Participants were recruited between 2014 and 2016. All participants underwent optical coherence tomography (OCT) imaging, including measurement of peripapillary retinal nerve fiber layer (pRNFL) thickness and total macular thickness (mRT). Participants did not show evidence of any significant ophthalmological conditions. Subgroup analyses were performed in participants with available MRI and CSF measures, providing evidence of neurodegeneration and underlying AD pathology respectively. // RESULTS: There was no evidence of overall between-group differences in pRNFL thickness (mean PCA 98.7 ± 12.2; tAD 99.9 ± 8.7; controls 99.6 ± 10.0 μm, one-way analysis of variance (ANOVA) p = 0.92) or total mRT (mean PCA 266.9 ± 16.3; tAD 267.8 ± 13.6; controls 269.3 ± 13.6 μm, one-way ANOVA p = 0.75). Similarly, subgroup analysis with MRI biomarkers (PCA = 18, tAD = 17, controls = 31) showing neurodegeneration, and CSF biomarkers (PCA = 18, tAD = 14, controls = 13) supporting underlying AD pathology did not provide evidence of overall between-group differences in pRNFL or mRT measures (all p > 0.3). // CONCLUSIONS: Retinal thickness did not discriminate tAD and PCA from controls or from one another despite unequivocal differences on standard clinical, neuro-imaging and CSF measures. Findings from this well-characterized sample, including cases with PCA, do not support the hypothesis that retinal neurodegeneration, measured using conventional OCT, is a useful biomarker for AD or PCA

Incidental cardiac findings on computed tomography imaging of the thorax

<p>Abstract</p> <p>Background</p> <p>Investigation of pulmonary pathology with computed tomography also allows visualisation of the heart and major vessels. We sought to explore whether clinically relevant cardiac pathology could be identified on computed tomography pulmonary angiograms (CTPA) requested for the exclusion of pulmonary embolism (PE). 100 consecutive CT contrast-enhanced pulmonary angiograms carried out for exclusion of PE at a single centre were assessed retrospectively by two cardiologists.</p> <p>Findings</p> <p>Evidence of PE was reported in 5% of scans. Incidental cardiac findings included: aortic wall calcification (54%), coronary calcification (46%), cardiomegaly (41%), atrial dilatation (18%), mitral annulus calcification (15%), right ventricular dilatation (11%), aortic dilatation (8%) and right ventricular thrombus (1%). Apart from 3 (3%) reports describing cardiomegaly, no other cardiac findings were described in radiologists' reports. Other reported pulmonary abnormalities included: lung nodules (14%), lobar collapse/consolidation (8%), pleural effusion (2%), lobar collapse/consolidation (8%), emphysema (6%) and pleural calcification (4%).</p> <p>Conclusions</p> <p>CTPAs requested for the exclusion of PE have a high yield of cardiac abnormalities. Although these abnormalities may not have implications for acute clinical management, they may, nevertheless, be important in long-term care.</p