Imaging of Tumor Hypoxia With 18F-EF5 PET/MRI in Cervical Cancer.

PURPOSE OF THE REPORT: The aim of this study was to evaluate the distribution of hypoxia using 18F-EF5 as a hypoxia tracer in cervical cancer patients with PET/MRI. We investigated the association between this 18F-EF5-PET tracer and the immunohistochemical expression of endogenous hypoxia markers: HIF1α, CAIX, and GLUT1. PATIENTS AND METHODS: Nine patients with biopsy-proven primary squamous cell cervix carcinoma (FIGO 2018 radiological stages IB1-IIIC2r) were imaged with dual tracers 18F-EF5 and 18F-FDG using PET/MRI (Int J Gynaecol Obstet. 2019;145:129-135). 18F-EF5 images were analyzed by calculating the tumor-to-muscle ratio to determine the hypoxic tissue (T/M ratio >1.5) and further hypoxic subvolume (HSV) and percentage hypoxic area. These 18F-EF5 hypoxic parameters were correlated with the size and localization of tumors in 18F-FDG PET/MRI and the results of hypoxia immunohistochemistry. RESULTS: All primary tumors were clearly 18F-FDG and 18F-EF5 PET positive and heterogeneously hypoxic with multiple 18F-EF5-avid areas in locally advanced cancer and single areas in clinically stage I tumors. The location of hypoxia was detected mainly in the periphery of tumor. Hypoxia parameters 18F-EF5 max T/M ratio and HSV in primary tumors correlated independently with the advanced stage (P = 0.036 and P = 0.040, respectively), and HSV correlated with the tumor size (P = 0.027). The location of hypoxia in 18F-EF5 imaging was confirmed with a higher hypoxic marker expression HIF1α and CAIX in tumor fresh biopsies. CONCLUSIONS: The 18F-EF5 imaging has promising potential in detecting areas of tumor hypoxia in cervical cancer.

Associations Between Brain Gray Matter Volumes and Adipose Tissue Metabolism in Healthy Adults.

OBJECTIVE: Gray matter (GM) volume in different brain loci has been shown to vary in obesity and diabetes, and elevated fasting plasma nonesterified fatty acid (NEFA) levels have been suggested as one potential mechanism. The hypothesis presented in this study is that brown adipose tissue (BAT) activity may correlate with GM volume in areas negatively associated with obesity and diabetes. METHODS: A total of 36 healthy patients (M/F: 12/24, age 39.7 ± 9.4 years, BMI 27.5 ± 5.6 kg/m2 ) were imaged with positron emission tomography using fatty acid analog [18 F]FTHA to measure NEFA uptake and with [15 O]H2 O to measure perfusion during cold exposure, at room temperature during fasting, or during a postprandial state. A 2-hour hyperinsulinemic euglycemic clamp was performed to measure whole-body insulin sensitivity (M value, mean 7.6 ± 3.9 mg/kg/min). T1-weighted magnetic resonance imaging at 1.5 T was performed on all patients. RESULTS: BAT NEFA uptake was associated directly with GM volume in anterior cerebellum and occipital lobe (P ≤ 0.04) when adjusted for age, gender, and intra-abdominal fat volume and with anterior cerebellum, limbic lobe, and temporal lobe GM volumes when adjusted for M value. CONCLUSIONS: BAT NEFA metabolism may participate in protection from cognitive degeneration associated with cardiometabolic risk factors, such as central obesity and insulin resistance. Potential causal relationships between BAT activity and GM volumes remain to be examined.

Changes in electrocardiogram parameters during acute nonshivering cold exposure and associations with brown adipose tissue activity, plasma catecholamine levels, and brachial blood pressure in healthy adults.

BACKGROUND: Sympathetic activity causes changes in electrocardiogram (ECG) during cold exposure and the changes have been studied mostly during hypothermia and less during mild acute nonshivering cold exposure. Cold-induced sympathetic activity also activates brown adipose tissue (BAT) and increases arterial blood pressure (BP) and plasma catecholamine levels. We examined changes in ECG parameters during acute nonshivering cold exposure and their associations with markers of sympathetic activity during cold exposure: brachial blood pressure (BP), plasma catecholamine levels, and BAT activity measured by positron emission tomography (PET). METHODS AND RESULTS: Healthy subjects (M/F = 13/24, aged 20-55 years) were imaged with [15 O]H2 O (perfusion, N = 37) and [18 F]FTHA to measure plasma nonesterified fatty acid uptake (NEFA uptake, N = 37) during 2-h nonshivering cold exposure. 12-lead ECG (N = 37), plasma catecholamine levels (N = 17), and brachial BP (N = 31) were measured at rest in room temperature (RT) and re-measured after a 2-h nonshivering cold exposure. There were significant differences between RT and cold exposure in P axis (35.6 ± 26.4 vs. 50.8 ± 22.7 degrees, p = 0.005), PR interval (177.7 ± 24.6 ms vs.163.0 ± 28.7 ms, p = 0.001), QRS axis (42.1 ± 31.3 vs. 56.9 ± 24.1, p = 0.003), and QT (411.7 ± 25.5 ms vs. 434.5 ± 39.3 ms, p = 0.001). There was no significant change in HR, QRS duration, QTc, JTc, and T axis during cold exposure. Systolic BP (127.2 ± 15.7 vs. 131.8 ± 17.9 mmHg, p = 0.008), diastolic BP (81.7 ± 12.0 vs. 85.4 ± 13.0 mmHg, p = 0.02), and plasma noradrenaline level increased during cold exposure (1.97 ± 0.61 vs. 5.07 ± 1.32 µmol/L, p = 0.001). Cold-induced changes in ECG parameters did not correlate with changes in BAT activity, brachial BP, plasma catecholamines, or skin temperature. CONCLUSIONS: During short-term nonshivering cold exposure, there were increases in P axis, PR interval, QRS axis, and QT compared to RT in healthy adults. Cold-induced changes in ECG parameters did not correlate with BAT activity, brachial BP, or plasma catecholamine levels which were used as markers of cold-induced sympathetic activity.

Resistance training improves skeletal muscle insulin sensitivity in elderly offspring of overweight and obese mothers.

AIMS/HYPOTHESIS: Maternal obesity predisposes offspring to adulthood morbidities, including type 2 diabetes. Type 2 diabetes and insulin resistance have been associated with shortened telomere length. First, we aimed to investigate whether or not maternal obesity influences insulin sensitivity and its relationship with leucocyte telomere length (LTL) in elderly women. Second, we tested whether or not resistance exercise training improves insulin sensitivity in elderly frail women. METHODS: Forty-six elderly women, of whom 20 were frail offspring of lean/normal weight mothers (OLM, BMI ≤26.3 kg/m2) and 17 were frail offspring of overweight/obese mothers (OOM,BMI ≥28.1 kg/m2), were studied before and after a 4 month resistance training (RT) intervention. Muscle insulin sensitivity of glucose uptake was measured using 18F-fluoro-2-deoxyglucose and positron emission tomography with computed tomography during a hyperinsulinaemic­euglycaemic clamp. Muscle mass and lipid content were measured using magnetic resonance and LTL was measured using real-time PCR. RESULTS: The OOM group had lower thigh muscle insulin sensitivity compared with the OLM group (p=0.048) but similar whole body insulin sensitivity. RT improved whole body and skeletal muscle insulin sensitivity in the OOM group only (p=0.004 and p=0.013, respectively), and increased muscle mass in both groups (p <0 .01). In addition, in the OOM group, LTL correlated with different thigh muscle groups insulin sensitivity (ρ ≥ 0.53; p ≤ 0.05). Individuals with shorter LTL showed a higher increase in skeletal muscle insulin sensitivity after training (ρ ≥ −0.61; p ≤ 0.05). CONCLUSIONS/INTERPRETATION: Maternal obesity and having telomere shortening were associated with insulin resistance in adult offspring. A resistance exercise training programme may reverse this disadvantage among offspring of obese mothers. Trial registration: ClinicalTrials.gov NCT01931540.

Plasminogen activator inhitor-1 associates with cardiovascular risk factors in healthy young adults in the Cardiovascular Risk in Young Finns Study.

AIMS: Hypofibrinolysis displayed by elevated serum plasminogen activator inhibitor 1 (PAI-1) level has been associated with cardiovascular disease (CVD) and its risk factors such as obesity and insulin resistance. However, no studies have examined associations between PAI-1 and CVD risk factors in healthy subjects. We examined associations between serum PAI-1, ultrasound markers of atherosclerosis and CVD risk factors and whether PAI-1 improves prediction of atherosclerosis over known risk factors in a cohort of asymptomatic adults. METHODS: We analyzed PAI-1 and CVD risk factors and assessed carotid intima-media thickness (cIMT), distensibility (CDist) and the presence of a carotid atherosclerotic plaque and flow-mediated dilation (FMD) ultrasonographically for 2202 adults (993 men and 1,209 women, aged 30-45 years) participating in the ongoing longitudinal cohort study, The Cardiovascular Risk in Young Finns Study. High cIMT was defined as >90th percentile and/or carotid plaque and low CDist and low FMD as <20th percentile. RESULTS: In bivariate analyses, PAI-1 correlated directly with cIMT and the risk factors: blood pressure, BMI, waist and hip circumference, alcohol use, total and LDL-cholesterol, triglycerides, glomerular filtration rate, high-sensitivity CRP and glucose (all P<0.005). PAI-1 was higher in men and increased with age. Inverse correlation was observed with CDist, HDL-cholesterol and adiponectin in both sexes, with testosterone and sex hormone binding globulin in men and with creatinine and oral contraceptive use in women (P<0.005). Independent direct associations were observed between PAI-1 and waist circumference, serum triglycerides, insulin, alcohol use and age and inverse with serum creatinine, HDL-cholesterol and adiponectin. PAI-1 did not improve estimation of high cIMT, low CDist and low FMD over conventional risk factors (P for difference in area under curve ≥ 0.37). CONCLUSION: PAI-1 was independently associated with several known CVD risk factors, especially obesity markers, in both men and women. However, addition of PAI-1 to known risk factors did not improve cross-sectional prediction of high cIMT, low CDist and low FMD suggesting that PAI-1 is not a clinically important biomarker in early atherosclerosis.

High-throughput quantification of circulating metabolites improves prediction of subclinical atherosclerosis.

AIMS: High-throughput metabolite quantification holds promise for cardiovascular risk assessment. Here, we evaluated whether metabolite quantification by nuclear magnetic resonance (NMR) improves prediction of subclinical atherosclerosis in comparison to conventional lipid testing. METHODS AND RESULTS: Circulating lipids, lipoprotein subclasses, and small molecules were assayed by NMR for 1595 individuals aged 24-39 years from the population-based Cardiovascular Risk in Young Finns Study. Carotid intima-media thickness (IMT), a marker of subclinical atherosclerosis, was measured in 2001 and 2007. Baseline conventional risk factors and systemic metabolites were used to predict 6-year incidence of high IMT (≥ 90 th percentile) or plaque. The best prediction of high intima-media thickness was achieved when total and HDL cholesterol were replaced by NMR-determined LDL cholesterol and medium HDL, docosahexaenoic acid, and tyrosine in prediction models with risk factors from the Framingham risk score. The extended prediction model improved risk stratification beyond established risk factors alone; area under the receiver operating characteristic curve 0.764 vs. 0.737, P =0.02, and net reclassification index 17.6%, P =0.0008. Higher docosahexaenoic acid levels were associated with decreased risk for incident high IMT (odds ratio: 0.74; 95% confidence interval: 0.67-0.98; P = 0.007). Tyrosine (1.33; 1.10-1.60; P = 0.003) and glutamine (1.38; 1.13-1.68; P = 0.001) levels were associated with 6-year incident high IMT independent of lipid measures. Furthermore, these amino acids were cross-sectionally associated with carotid IMT and the presence of angiographically ascertained coronary artery disease in independent populations. CONCLUSION: High-throughput metabolite quantification, with new systemic biomarkers, improved risk stratification for subclinical atherosclerosis in comparison to conventional lipids and could potentially be useful for early cardiovascular risk assessment.

Tracking of noninvasive ultrasound measurements of subclinical atherosclerosis in adulthood: findings from the Cardiovascular Risk in Young Finns Study.

We examined tracking of ultrasound measurements of vascular structure and function in adulthood using data collected in the 2001 and 2007 follow-ups of Cardiovascular Risk in Young Finns Study. B-mode ultrasound measures of carotid artery intima-media thickness (IMT), carotid artery distensibility (CDist) and brachial artery flow-mediated dilatation (FMD) was obtained on 1809 apparently healthy Finnish adults aged 24 to 39 years in 2001 (1014 females; 795 males). Significant 6-year tracking was observed for IMT (males, r = 0.56; females, r = 0.46), CDist (males, r = 0.35; females, r = 0.36) and FMD (males, r = 0.23; females, r = 0.20). Subjects with 10-year risk of CVD (according to the SCORE risk score) above sex-specific median had improved IMT (r = 0.44; r = 0.57, p = 0.0001) and CDist (r = 0.31; r = 0.40, p = 0.03) tracking compared with those below median. Body mass index (BMI) >or= 30 kg/m(2) decreased tracking of CDist (r = 0.36; r = 0.19, p = 0.01). In conclusion, ultrasound measurements tracked low to moderate over 6-years and was influenced by cardiovascular disease (CVD) risk factor status.

Cardiovascular risk scores in the prediction of subclinical atherosclerosis in young adults: evidence from the cardiovascular risk in a young Finns study.

AIM: To study the utility of risk scores in the prediction of subclinical atherosclerosis in young adults. METHODS AND RESULTS: Participants were 2204 healthy Finnish adults aged 24-39 years in 2001 from a population-based follow-up study Cardiovascular Risk in Young Finns. We examined the performance of the Framingham, Reynolds, Systematic Coronary Risk Evaluation (SCORE), PROCAM, and Finrisk cardiovascular risk scores to predict subclinical atherosclerosis, that is carotid artery intima-media thickness (IMT) and plaque, carotid artery distensibility (CDist), and brachial artery flow-mediated dilatation (FMD) 6 years later. In a 6-year prediction of high IMT (highest decile or plaque), areas under the receiver operating characteristic curves (AUC) for baseline Finrisk (0.733), SCORE (0.726), PROCAM (0.712), and Reynolds (0.729) risk scores were similar as for Framingham risk score (0.728, P always ≥0.15). All risk scores had a similar discrimination in predicting low CDist (lowest decile) (0.652, 0.642, 0.639, 0.658, 0.652 respectively, P always ≥0.41). In the prediction of low FMD (lowest decile), Finrisk, PROCAM, Reynolds, and Framingham scores had similar AUCs (0.578, 0.594, 0.582, 0.568, P always ≥0.08) and SCORE discriminated slightly better (AUC=0.596, P<0.05). The prediction of subclinical outcomes was consistent when estimated from other statistical measures of discrimination, reclassification, and calibration. CONCLUSION: Cardiovascular disease risk scores had equal value in predicting subclinical atherosclerosis measured by IMT and CDist in young adults. SCORE was more accurate in predicting low FMD than Framingham risk score.