Context
Children with cancer undergoing chemotherapy experience a cluster of psychoneurological symptoms (PNS), including pain, fatigue, anxiety, and depressive symptoms. Metabolomics is promising to ...differentiate metabolic pathways associated with the PNS cluster.
Objectives
Identify metabolic pathways associated with the PNS cluster in children with cancer before and after chemotherapy.
Methods
Pain, fatigue, anxiety, and depressive symptoms were assessed using the Pediatric PROMIS scales. T-scores were computed and divided dichotomously by a cutoff point of 50; the PNS cluster was a sum of the four symptoms ranging from 0 (all T-scores <50) to 4 (all T-scores ≥50). Serum metabolites were processed using liquid chromatography mass-spectrometry untargeted metabolomics approach. Linear regression models examined metabolites associated with the PNS cluster. Metabolic pathway enrichment analysis was performed.
Results
Participant demographics (n = 40) were 55% female, 60% white, 62.5% aged 13–19 years, and 62.5% diagnoses of Hodgkin’s lymphoma and B-cell acute lymphocytic leukemia. Among 9276 unique metabolic features, 454 were associated with pain, 281 with fatigue, 596 with anxiety, 551 with depressive symptoms, and 300 with the PNS cluster across one chemotherapy cycle. Fatty acids pathways were associated with pain: de novo fatty acid biosynthesis (p < .001), fatty acid metabolism (p = .001), fatty acid activation (p = .004), and omega-3 fatty acid metabolism (p = .009). Tryptophan amino acid pathway was associated with fatigue (p < .001), anxiety (p = .015), and the PNS cluster (p = .037). Carnitine shuttle was associated with the PNS cluster (p = .015).
Conclusion
Fatty acids and amino acids pathways were associated with PNS in children undergoing chemotherapy. These findings require further investigation in a larger sample.
Factors suspected of causing certain chronic diseases and death are often associated with lower mortality among those with disease. For end-stage renal disease, examples include high cholesterol and ...homocysteine. Here, we consider obesity, thought to cause both end-stage renal disease and premature mortality, but which is associated with lower mortality among end-stage renal disease patients. Such seeming paradoxes could reflect collider (index event) bias due to selection of a diseased population for study. However, previous descriptions are incomplete, as they posit an uncontrolled factor causing both end-stage renal disease (the index event) and death. Here, we explicitly note that death can precede end-stage renal disease onset. The target population is obese persons with end-stage renal disease, effects of interest are seemingly controlled direct effects, the usual estimator is a conditional risk ratio, and remaining at risk until the onset of end-stage renal disease is a collider. Collider bias is then expected if any mortality risk factor is uncontrolled, even if no factor also affects end-stage renal disease. The bias is similar to, but differs from, that associated with competing risks. Because control of every mortality risk factor is implausible, bias of the standard estimator is practically unavoidable. Better awareness of these issues by clinicians and researchers is needed if observational research is to usefully guide care of this vulnerable patient population.
Smoking is an established risk factor for a human papillomavirus (HPV) infection advancing to cervical precancer and cancer, but its role earlier in the natural history is less clear. Smoking is ...inversely associated with possessing HPV antibodies from a past infection suggesting that smoking may influence acquiring subsequent infections.
In a cohort of 1976 U.S. women, we evaluate whether reduced antibodies to HPV-16 is a mechanism for smoking's role on acquiring a subsequent HPV-16 infection, through the analytic technique of causal mediation analysis. We posit a causal model and estimate two counterfactually defined effects: a smoking impaired antibody-mediated indirect effect and a nonmediated direct effect representing all other potential mechanisms of smoking.
Compared to never smokers, current smokers had increased odds of HPV-16 infection by the antibody-mediated indirect effect (odds ratio OR = 1.29; 95% confidence interval CI: 1.11, 1.73); the estimated direct effect was very imprecise (OR = 0.57; 95% CI, 0.26–1.13). We observed a stronger estimated indirect effect among women who smoked at least half a pack of cigarettes daily (OR = 1.61, 95% CI, 1.27–2.15) than among women who smoked less than that threshold (OR = 1.09; 95% CI, 0.94–1.44).
This is the first study to directly test the mechanism underlying smoking as an HPV cofactor. The results support current smoking as a risk factor earlier in the natural history of HPV and are consistent with the hypothesis that smoking increases the risk of a subsequent infection by reducing immunity.
There is growing evidence that the metabolism is deeply intertwined with head and neck squamous cell carcinoma (HNSCC) progression and survival but little is known about circulating metabolite ...patterns and their clinical potential. We performed unsupervised hierarchical clustering of 209 HNSCC patients via pre-treatment plasma metabolomics to identify metabolic subtypes. We annotated the subtypes via pathway enrichment analysis and investigated their association with overall and progression-free survival. We stratified the survival analyses by smoking history. High-resolution metabolomics extracted 186 laboratory-confirmed metabolites. The optimal model created two patient clusters, of subtypes A and B, corresponding to 41% and 59% of the study population, respectively. Fatty acid biosynthesis, acetyl-CoA transport, arginine and proline, as well as the galactose metabolism pathways differentiated the subtypes. Relative to subtype B, subtype A patients experienced significantly worse overall and progression-free survival but only among ever-smokers. The estimated three-year overall survival was 61% for subtype A and 86% for subtype B; log-rank
= 0.001. The association with survival was independent of HPV status and other HNSCC risk factors (adjusted hazard ratio = 3.58, 95% CI: 1.46, 8.78). Our findings suggest that a non-invasive metabolomic biomarker would add crucial information to clinical risk stratification and raise translational research questions about testing such a biomarker in clinical trials.
Epigenetic age acceleration (EAA) is robustly linked with mortality and morbidity. This study examined risk factors of EAA and its association with overall survival (OS), progression-free survival ...(PFS), and quality of life (QOL) in patients with head and neck cancer (HNC) receiving radiation therapy.
Patients without distant metastasis were enrolled and followed before and at the end of radiation therapy and at 6 and 12 months after radiation therapy. EAA was calculated with DNAmPhenoAge at all 4 time points. Risk factors included demographic characteristics, lifestyle, clinical characteristics, treatment-related symptoms, and blood biomarkers. Survival data were collected until August 2020, and QOL was measured using Functional Assessment of Cancer Therapy-HNC.
Increased comorbidity, symptoms unrelated to human papilloma virus, and more severe treatment-related symptoms were associated with higher EAA (P = .03 to P < .001). A nonlinear association (quadratic) between body mass index (BMI) and EAA was observed: decreased BMI (<35 kg/m
; P = .04) and increased BMI (≥35 kg/m
; P = .01) were linked to higher EAA. Increased EAA (per year) was associated with worse OS (hazard ratio HR, 1.11 95% confidence interval {CI}, 1.03-1.18; P = .004; HR, 1.10 95% CI, 1.01-1.19; P = .02 for EAA at 6 and 12 months after treatment, respectively) and PFS (HR, 1.10 95% CI, 1.02-1.19; P = .02; HR, 1.14 95% CI, 1.06-1.23; P < .001; and HR, 1.08 95% CI, 1.02-1.14; P = .01) for EAA before, immediately after, and 6 months after radiation therapy, respectively) and QOL over time (β = -0.61; P = .001). An average of 3.25 to 3.33 years of age acceleration across time, which was responsible for 33% to 44% higher HRs of OS and PFS, was observed in those who died or developed recurrence compared with those who did not (all P < .001).
Compared with demographic and lifestyle factors, clinical characteristics were more likely to contribute to faster biological aging in patients with HNC. Acceleration in epigenetic age resulted in more aggressive adverse events, including OS and PFS. EAA could be considered as a marker for cancer outcomes, and decelerating aging could improve survival and QOL.
Ninety-million Americans suffer metabolic syndrome (MetSyn), increasing the risk of diabetes and poor brain outcomes, including neuropathology linked to lower cerebral blood flow (CBF), predominantly ...in anterior regions. We tested the hypothesis that total and regional CBF is lower in MetSyn more so in the anterior brain and explored three potential mechanisms. Thirty-four controls (25 ± 5 yr) and 19 MetSyn (30 ± 9 yr), with no history of cardiovascular disease/medications, underwent four-dimensional flow magnetic resonance imaging (MRI) to quantify macrovascular CBF, whereas arterial spin labeling quantified brain perfusion in a subset (
= 38/53). Contributions of cyclooxygenase (COX;
= 14), nitric oxide synthase (NOS,
= 17), or endothelin receptor A signaling (
= 13) were tested with indomethacin,
-monomethyl-L-arginine (L-NMMA), and Ambrisentan, respectively. Total CBF was 20 ± 16% lower in MetSyn (725 ± 116 vs. 582 ± 119 mL/min,
< 0.001). Anterior and posterior brain regions were 17 ± 18% and 30 ± 24% lower in MetSyn; reductions were not different between regions (
= 0.112). Global perfusion was 16 ± 14% lower in MetSyn (44 ± 7 vs. 36 ± 5 mL/100 g/min,
= 0.002) and regionally in frontal, occipital, parietal, and temporal lobes (range 15-22%). The decrease in CBF with L-NMMA (
= 0.004) was not different between groups (
= 0.244,
= 14, 3), and Ambrisentan had no effect on either group (
= 0.165,
= 9, 4). Interestingly, indomethacin reduced CBF more in Controls in the anterior brain (
= 0.041), but CBF decrease in posterior was not different between groups (
= 0.151,
= 8, 6). These data indicate that adults with MetSyn exhibit substantially reduced brain perfusion without regional differences. Moreover, this reduction is not due to loss of NOS or gain of ET-1 signaling but rather a loss of COX vasodilation.
We tested the impact of insulin resistance (IR) on resting cerebral blood flow (CBF) in adults with metabolic syndrome (MetSyn). Using MRI and research pharmaceuticals to study the role of NOS, ET-1, or COX signaling, we found that adults with MetSyn exhibit substantially lower CBF that is not explained by changes in NOS or ET-1 signaling. Interestingly, adults with MetSyn show a loss of COX-mediated vasodilation in the anterior but not posterior circulation.
Integrating brain imaging with large scale omics data may identify novel mechanisms of mild cognitive impairment (MCI) and early Alzheimer's disease (AD). We integrated and analyzed brain magnetic ...resonance imaging (MRI) with cerebrospinal fluid (CSF) metabolomics to elucidate metabolic mechanisms and create a "metabolic map" of the brain in prodromal AD.
In 145 subjects (85 cognitively normal controls and 60 with MCI), we derived voxel-wise gray matter volume via whole-brain structural MRI and conducted high-resolution untargeted metabolomics on CSF. Using a data-driven approach consisting of partial least squares discriminant analysis, a multiomics network clustering algorithm, and metabolic pathway analysis, we described dysregulated metabolic pathways in CSF mapped to brain regions associated with MCI in our cohort.
The multiomics network algorithm clustered metabolites with contiguous imaging voxels into seven distinct communities corresponding to the following brain regions: hippocampus/parahippocampal gyrus (three distinct clusters), thalamus, posterior thalamus, parietal cortex, and occipital lobe. Metabolic pathway analysis indicated dysregulated metabolic activity in the urea cycle, and many amino acids (arginine, histidine, lysine, glycine, tryptophan, methionine, valine, glutamate, beta-alanine, and purine) was significantly associated with those regions (
< 0.05).
By integrating CSF metabolomics data with structural MRI data, we linked specific AD-susceptible brain regions to disrupted metabolic pathways involving nitrogen excretion and amino acid metabolism critical for cognitive function. Our findings and analytical approach may extend drug and biomarker research toward more multiomics approaches.
Inflammation is proposed to increase risk of developing endometrial cancer, but few prospective epidemiologic studies have investigated the relationship between circulating inflammation markers and ...endometrial cancer risk. In a nested case‐control study within the PLCO Screening Trial we measured serum levels of 64 inflammation‐related biomarkers in 284 incident endometrial cancer cases and 284 matched controls. Using multivariable logistic regression inflammation markers were evaluated individually and combined into a cross‐validated inflammation score. Of 64 markers, 22 were associated with endometrial cancer risk at p < 0.05 and 17 of 22 markers remained associated after multiple testing corrections. After adjusting for BMI and estradiol, SERPINE1 quartile(Q)4 vs. Q1 odds ratio (OR) (95% confidence interval (CI)), p trend = 2.43 (0.94–6.29), 0.03 and VEGFA 2.56 (1.52–4.30), 0.0002 were positively associated with endometrial cancer risk, while CCL3 0.46 (0.27–0.77), 0.01, IL13 0.55 (0.33–0.93), 0.01, IL21 0.52 (0.31–0.87), 0.01, IL1B 0.51 (0.30–0.86), 0.01 and IL23 0.60 (0.35–1.03), 0.02 were inversely associated with risk. We observed large differences in ORs across BMI‐inflammation score categories. Endometrial cancer risk was most pronounced among obese women with the highest inflammation score tertile (T) 10.25 (3.56–29.55) vs. normal BMI/T1. Several inflammation markers were prospectively associated with endometrial cancer, including adipokines, pro‐ and anti‐inflammatory cytokines, angiogenic factors and acute phase proteins. Inverse associations with anti‐inflammatory markers (IL13, IL21), other inflammation markers/mediators (CCL3, IL1B, IL23), and a robust positive association between VEGFA and endometrial cancer risk were independent of BMI and estradiol, suggesting that these factors may influence risk through other mechanisms.
What's new?
Can circulating inflammation markers predict endometrial cancer? Rising rates of endometrial cancer have been attributed to fewer hysterectomies and more obesity. Inflammation has also been suggested as a contributor, but less evidence supports this association. These authors conducted the most comprehensive evaluation to date of pro‐ and anti‐inflammatory markers in endometrial cancer. While many of the inflammatory marker associations they found disappeared after accounting for BMI or circulating estradiol, they did find an independent association between pro‐inflammatory marker VEGFA and endometrial cancer risk. Several anti‐inflammatory markers inversely associated with cancer risk as well, independent of BMI and estradiol.
Translating relative risk estimates into absolute risks is important in evaluating the potential clinical and public health relevance of etiologic discoveries. Predicting high absolute risk is ...challenging, particularly for rare endpoints such as pancreatic cancer. Recent efforts to develop risk prediction models for pancreatic cancer have found moderate risk levels for very small parts of the population. A new approach in which clinical symptoms and medication use are evaluated in addition to information on risk factors is presented by Risch et al. in this issue of the Journal (Am J Epidemiol. 2015;182(1):26-34). The authors estimated absolute risks based on the relative risks obtained from their case-control study. Their absolute risk estimates were higher than those from previous approaches but remained restricted to a very small proportion of the general population. In the present commentary, we address issues of absolute risk stratification (particularly for rare diseases), specific analytic methods, and how actionable information will differ based on the disease and possible intervention. We suggest that moving from cancer-specific models to broader models used to predict risk for multiple outcomes can make risk prediction for rare diseases more effective. When considering translational goals, it is important to estimate absolute risk at the early stages of etiologic research. The results can be sobering but allow focusing on the most promising goals.
Established prognostic factors for head and neck squamous cell carcinoma (HNSCC) mostly consist of clinical and tumor features assessed before treatment. We report a novel application of DNA ...methylation in peripheral blood before and after radiation therapy to further improve outcomes stratification.
Peripheral blood samples from patients with nonmetastatic HNSCC were obtained for methylation analysis 1 week before and 1 month after radiation therapy. Patients were randomized 1:1 to a Discovery Cohort or a Validation Cohort. In the Discovery Cohort, associations between genome-wide methylation change (posttreatment minus pretreatment) and recurrence-free survival (RFS) as well as overall survival (OS) were evaluated using Cox regression. A methylation risk score (MRS) was then constructed from methylation levels at the top associated sites, filtered for residing within the regulatory regions of genes expressed in cells of hematopoietic lineage. The prognostic value of MRS was separately assessed in the Discovery and Validation Cohorts.
Between December 2013 and September 2018, 115 patients participated in this study. Human papilloma virus negative status, oral cavity cancer, gastrostomy tube insertion, and higher neutrophil count before radiation therapy were associated with shorter RFS and OS (P < .05). Genes downstream of the methylation sites comprising MRS are HIF1A, SF1, LGALS9, and FUT5, involved in hypoxia response, blood cell maturation, and immune modulation. High MRS (in the top third) was significantly associated with worse RFS (hazard ratio HR, 7.1; 95% confidence interval CI, 1.4-35.5; P = .016) and OS (HR, 15.9; 95% CI, 1.6-153.6; P = .017) in the Discovery Cohort, independent of the aforementioned risk factors. These findings were replicated in the Validation Cohort, for which high MRS also independently predicted worse RFS (HR, 10.2; 95%, CI 2.4-43.4; P = .002) and OS (HR, 3.7; 95% CI, 1.3-10.4; P = .015).
We successfully trained and validated a signature of DNA methylation in peripheral blood before and after radiation therapy that stratified outcomes among patients with HNSCC, implicating the potential for genomics-tailored surveillance and consolidation treatment.
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