Monitoring Early Response to Anti-Angiogenic Therapy: Diffusion-Weighted Magnetic Resonance Imaging and Volume Measurements in Colon Carcinoma Xenografts

Objectives

To evaluate the use of diffusion-weighted MRI (DW-MRI) and volume measurements for early monitoring of antiangiogenic therapy in an experimental tumor model.

Materials and Methods

23 athymic nude rats, bearing human colon carcinoma xenografts (HT-29) were examined before and after 6 days of treatment with regorafenib (n = 12) or placebo (n = 11) in a clinical 3-Tesla MRI. For DW-MRI, a single-shot EPI sequence with 9 b-values (10–800 s/mm²) was used. The apparent diffusion coefficient (ADC) was calculated voxelwise and its median value over a region of interest, covering the entire tumor, was defined as the tumor ADC. Tumor volume was determined using T2-weighted images. ADC and volume changes between first and second measurement were evaluated as classifiers by a receiver-operator-characteristic (ROC) analysis individually and combined using Fisher''s linear discriminant analysis (FLDA).

Results

All ADCs and volumes are stated as median±standard deviation. Tumor ADC increased significantly in the therapy group (0.76±0.09×10⁻³ mm²/s to 0.90±0.12×10⁻³ mm²/s; p<0.001), with significantly higher changes of tumor ADC than in the control group (0.10±0.11×10⁻³ mm²/s vs. 0.03±0.09×10⁻³ mm²/s; p = 0.027). Tumor volume increased significantly in both groups (therapy: 347.8±449.1 to 405.3±823.6 mm³; p = 0.034; control: 219.7±79.5 to 443.7±141.5 mm³; p<0.001), however, the therapy group showed significantly reduced tumor growth (33.30±47.30% vs. 96.43±31.66%; p<0.001). Area under the curve and accuracy of the ADC-based ROC analysis were 0.773 and 78.3%; and for the volume change 0.886 and 82.6%. The FLDA approach yielded an AUC of 0.985 and an accuracy of 95.7%.

Conclusions

Regorafenib therapy significantly increased tumor ADC after 6 days of treatment and also significantly reduced tumor growth. However, ROC analyses using each parameter individually revealed a lack of accuracy in discriminating between therapy and control group. The combination of both parameters using FLDA substantially improved diagnostic accuracy, thus highlighting the potential of multi-parameter MRI as an imaging biomarker for non-invasive early tumor therapy monitoring.     

Quantification of Tumor Vessels in Glioblastoma Patients Using Time-of-Flight Angiography at 7 Tesla: A Feasibility Study

Purpose

To analyze if tumor vessels can be visualized, segmented and quantified in glioblastoma patients with time of flight (ToF) angiography at 7 Tesla and multiscale vessel enhancement filtering.

Materials and Methods

Twelve patients with newly diagnosed glioblastoma were examined with ToF angiography (TR = 15 ms, TE = 4.8 ms, flip angle = 15°, FOV = 160×210 mm², voxel size: 0.31×0.31×0.40 mm³) on a whole-body 7 T MR system. A volume of interest (VOI) was placed within the border of the contrast enhancing part on T1-weighted images of the glioblastoma and a reference VOI was placed in the non-affected contralateral white matter. Automated segmentation and quantification of vessels within the two VOIs was achieved using multiscale vessel enhancement filtering in ImageJ.

Results

Tumor vessels were clearly visible in all patients. When comparing tumor and the reference VOI, total vessel surface (45.3±13.9 mm² vs. 29.0±21.0 mm² (p<0.035)) and number of branches (3.5±1.8 vs. 1.0±0.6 (p<0.001) per cubic centimeter were significantly higher, while mean vessel branch length was significantly lower (3.8±1.5 mm vs 7.2±2.8 mm (p<0.001)) in the tumor.

Discussion

ToF angiography at 7-Tesla MRI enables characterization and quantification of the internal vascular morphology of glioblastoma and may be used for the evaluation of therapy response within future studies.     

18F-FDG PET Metabolic Parameters and MRI Perfusion and Diffusion Parameters in Hepatocellular Carcinoma: A Preliminary Study

Objectives

Glucose metabolism, perfusion, and water diffusion may have a relationship or affect each other in the same tumor. The understanding of their relationship could expand the knowledge of tumor characteristics and contribute to the field of oncologic imaging. The purpose of this study was to evaluate the relationships between metabolism, vasculature and cellularity of advanced hepatocellular carcinoma (HCC), using multimodality imaging such as ¹⁸F-FDG positron emission tomography (PET), dynamic contrast enhanced (DCE)-MRI, and diffusion weighted imaging(DWI).

Materials and Methods

Twenty-one patients with advanced HCC underwent ¹⁸F-FDG PET, DCE-MRI, and DWI before treatment. Maximum standard uptake values (SUV_max) from ¹⁸F-FDG-PET, variables of the volume transfer constant (K^trans) from DCE-MRI and apparent diffusion coefficient (ADC) from DWI were obtained for the tumor and their relationships were examined by Spearman’s correlation analysis. The influence of portal vein thrombosis on SUV_max and variables of K^trans and ADC was evaluated by Mann-Whitney test.

Results

SUV_max showed significant negative correlation with K^trans _max (ρ = −0.622, p = 0.002). However, variables of ADC showed no relationship with variables of K^trans or SUV_max (p>0.05). Whether portal vein thrombosis was present or not did not influence the SUV _max and variables of ADC and K^trans (p>0.05).

Conclusion

In this study, SUV was shown to be correlated with K_trans in advanced HCCs; the higher the glucose metabolism a tumor had, the lower the perfusion it had, which might help in guiding target therapy.     

Cardio-Respiratory Reference Data in 4631 Healthy Men and Women 20-90 Years: The HUNT 3 Fitness Study

Purpose

To provide a large reference material on key cardio-respiratory variables in a healthy population of Norwegian men and women aged 20–90 years.

Methods

Sub maximal and peak levels of cardio-respiratory variables were measured using cardiopulmonary exercise testing during treadmill running.

Results

The highest peak ventilation among men (141.9±24.5 L·min⁻¹) and women (92.0±16.5 L·min⁻¹) was observed in the youngest age group (20–29 years, sex differences p<0.001) with an average 7% reduction per decade. The highest tidal volumes were observed in the 30–39 and 40–49 year age groups among men (2.94±0.46 L) and women (2.06±0.32 L) (sex differences p<0.001), with a subsequent average 6% reduction per decade. Ventilatory threshold and respiratory compensation point were observed at approximately 77% and 87% of peak oxygen uptake (VO_2peak) among men and women, respectively. The best ventilatory efficiency (EqVCO_2Than) was observed in the youngest age group (20–29 years) in both men (26.2±2.8) and woman (27.5±2.7) (sex differences p<0.001) with an average 3% deterioration in ventilatory efficiency per decade.

Conclusion

This is the largest European reference material of cardio-respiratory variables in healthy men and women aged 20–90 years, establishing normal values for, and associations between key cardio-respiratory parameters. This will be useful in clinical decision making when evaluating cardiopulmonary health in similar populations.     

Multimodal Retinal Vessel Analysis in CADASIL Patients

Purpose

To further elucidate retinal findings and retinal vessel changes in Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients by means of high resolution retinal imaging.

Methods

28 eyes of fourteen CADASIL patients and an equal number of control subjects underwent confocal scanning laser ophthalmoscopy (cSLO), spectral-domain optical coherence tomography (SD-OCT), retinal nerve fibre layer (RNFL) measurements, fluorescein and indocyanine angiography. Three vessel measurement techniques were applied: RNFL thickness, a semiautomatic software tool based on cSLO images and manual vessel outlining based on SD-OCT.

Results

Mean age of patients was 56.2±11.6 years. Arteriovenous nicking was present in 22 (78.6%) eyes and venous dilation in 24 (85.7%) eyes. Retinal volume and choroidal volume were 8.77±0.46 mm³ and 8.83±2.24 mm³. RNFL measurements showed a global increase of 105.2 µm (Control group: 98.4 µm; p = 0.015). Based on semi-automatic cSLO measurements, maximum diameters of arteries and veins were 102.5 µm (106.0 µm; p = 0.21) and 128.6 µm (124.4 µm; p = 0.27) respectively. Manual SD-OCT measurements revealed significantly increased mean arterial 138.7 µm (125.4 µm; p<0.001) and venous 160.0 µm (146.9; p = 0.003) outer diameters as well as mean arterial 27.4 µm (19.2 µm; p<0.001) and venous 18.3 µm (15.7 µm; p<0.001) wall thicknesses in CADASIL patients.

Conclusions

The findings reflect current knowledge on pathophysiologic changes in vessel morphology in CADASIL patients. SD-OCT may serve as a complementary tool to diagnose and follow-up patients suffering from cerebral small-vessel diseases.     

Cardiac Compression of Lung Lower Lobes after Coronary Artery Bypass Graft with Cardiopulmonary Bypass

Background

Atelectasis is a major cause of hypoxemia after coronary artery bypass grafting (CABG) and is commonly ascribed to general anesthesia, high inspiratory oxygen concentration and cardiopulmonary bypass (CPB). The objective of this study was to evaluate the role of heart-induced pulmonary compression after CABG with CPB.

Methods

Seventeen patients without pre-operative cardiac failure who were scheduled for coronary artery bypass graft underwent pre- and postoperative thoracic computed tomography. The cardiac mass, the pressure exerted on the lungs by the right and left heart and the fraction of collapsed lower lobe segments below and outside of the heart limits were evaluated on a computed tomography section 1 cm above the diaphragmatic cupola.

Results

In the postoperative period, cardiac mass increased by 32% (117±31 g versus 155±35 g, p<0.001), leading to an increase in the pressure that was exerted on the lungs by the right (2.2±0.6 g.cm⁻² versus 3.2±1.2 g.cm⁻², p<0.05) and left heart (2.4±0.7 g.cm⁻² versus 4.2±1.8 g.cm⁻², p<0.001). The proportion of collapsed lung segments beneath the heart markedly increased [from 6.7% to 32.9% on the right side (p<0.001) and from 6.2% to 29% on the left side (p<0.001)], whereas the proportion of collapsed lung segments outside of the heart limits slightly increased [from 0.7% to 10.8% on the right side (p<0.001) and from 1.5% to 12.6% on the left side (p<0.001)].

Conclusion

The pressure that is exerted by the heart on the lungs increased postoperatively and contributed to the collapse of subjacent pulmonary segments.     

Differentiation between Primary Cerebral Lymphoma and Glioblastoma Using the Apparent Diffusion Coefficient: Comparison of Three Different ROI Methods

Objective

Apparent diffusion coefficients (ADC) can help differentiate between central nervous system (CNS) lymphoma and Glioblastoma (GBM). However, overlap between ADCs for GBM and lymphoma have been reported because of various region of interest (ROI) methods. Our aim is to explore ROI method to provide the most reproducible results for differentiation.

Materials and Methods

We studied 25 CNS lymphomas and 62 GBMs with three ROI methods: (1) ROI₁, whole tumor volume; (2) ROI₂, multiple ROIs; and (3) ROI₃, a single ROI. Interobserver variability of two readers for each method was analyzed by intraclass correlation(ICC). ADCs were compared between GBM and lymphoma, using two-sample t-test. The discriminative ability was determined by ROC analysis.

Results

ADCs from ROI₁ showed most reproducible results (ICC >0.9). For ROI₁, ADC_mean for lymphoma showed significantly lower values than GBM (p = 0.03). The optimal cut-off value was 0.98×10⁻³ mm²/s with 85% sensitivity and 90% specificity. For ROI₂, ADC_min for lymphoma was significantly lower than GBM (p = 0.02). The cut-off value was 0.69×10⁻³ mm²/s with 87% sensitivity and 88% specificity.

Conclusion

ADC values were significantly dependent on ROI method. ADCs from the whole tumor volume had the most reproducible results. ADC_mean from the whole tumor volume may aid in differentiating between lymphoma and GBM. However, multi-modal imaging approaches are recommended than ADC alone for differentiation.     

Comparison of Texture Features Derived from Static and Respiratory-Gated PET Images in Non-Small Cell Lung Cancer

Background

PET-based texture features have been used to quantify tumor heterogeneity due to their predictive power in treatment outcome. We investigated the sensitivity of texture features to tumor motion by comparing static (3D) and respiratory-gated (4D) PET imaging.

Methods

Twenty-six patients (34 lesions) received 3D and 4D [¹⁸F]FDG-PET scans before the chemo-radiotherapy. The acquired 4D data were retrospectively binned into five breathing phases to create the 4D image sequence. Texture features, including Maximal correlation coefficient (MCC), Long run low gray (LRLG), Coarseness, Contrast, and Busyness, were computed within the physician-defined tumor volume. The relative difference (δ_3D-4D) in each texture between the 3D- and 4D-PET imaging was calculated. Coefficient of variation (CV) was used to determine the variability in the textures between all 4D-PET phases. Correlations between tumor volume, motion amplitude, and δ_3D-4D were also assessed.

Results

4D-PET increased LRLG ( = 1%–2%, p<0.02), Busyness ( = 7%–19%, p<0.01), and decreased MCC ( = 1%–2%, p<7.5×10⁻³), Coarseness ( = 5%–10%, p<0.05) and Contrast ( = 4%–6%, p>0.08) compared to 3D-PET. Nearly negligible variability was found between the 4D phase bins with CV<5% for MCC, LRLG, and Coarseness. For Contrast and Busyness, moderate variability was found with CV = 9% and 10%, respectively. No strong correlation was found between the tumor volume and δ_3D-4D for the texture features. Motion amplitude had moderate impact on δ for MCC and Busyness and no impact for LRLG, Coarseness, and Contrast.

Conclusions

Significant differences were found in MCC, LRLG, Coarseness, and Busyness between 3D and 4D PET imaging. The variability between phase bins for MCC, LRLG, and Coarseness was negligible, suggesting that similar quantification can be obtained from all phases. Texture features, blurred out by respiratory motion during 3D-PET acquisition, can be better resolved by 4D-PET imaging. 4D-PET textures may have better prognostic value as they are less susceptible to tumor motion.     

Reduced Basal ATP Synthetic Flux of Skeletal Muscle in Patients with Previous Acromegaly

Background

Impaired mitochondrial function and ectopic lipid deposition in skeletal muscle and liver have been linked to decreased insulin sensitivity. As growth hormone (GH) excess can reduce insulin sensitivity, we examined the impact of previous acromegaly (AM) on glucose metabolism, lipid storage and muscular ATP turnover.

Participants and Methods

Seven AM (4f/3 m, age: 46±4 years, BMI: 28±1 kg/m²) and healthy volunteers (CON: 3f/4 m, 43±4 years, 26±2 kg/m²) matched for age and body mass underwent oral glucose testing for assessment of insulin sensitivity (OGIS) and ß-cell function (adaptation index, ADAP). Whole body oxidative capacity was measured with indirect calorimetry and spiroergometry. Unidirectional ATP synthetic flux (fATP) was assessed from ³¹P magnetic resonance spectroscopy (MRS) of calf muscle. Lipid contents of tibialis anterior (IMCLt) and soleus muscles (IMCLs) and liver (HCL) were measured with ¹H MRS.

Results

Despite comparable GH, insulin-like growth factor-1 (IGF-I) and insulin sensitivity, AM had ∼85% lower ADAP (p<0.01) and ∼21% reduced VO₂max (p<0.05). fATP was similarly ∼25% lower in AM (p<0.05) and related positively to ADAP (r = 0.744, p<0.01), but negatively to BMI (r = −0.582, p<0.05). AM had ∼3fold higher HCL (p<0.05) while IMCLt and IMCLs did not differ between the groups.

Conclusions

Humans with a history of acromegaly exhibit reduced insulin secretion, muscular ATP synthesis and oxidative capacity but elevated liver fat content. This suggests that alterations in ß-cell function and myocellular ATP production may persist despite normalization of GH secretion after successful treatment of acromegaly.     

Comparison of Methods to Reduce Myocardial 18F-FDG Uptake in Mice: Calcium Channel Blockers versus High-Fat Diets

Purpose

Besides its application in oncology, ¹⁸F-FDG PET-CT imaging is also useful in the diagnosis of certain lung infections, inflammatory diseases, and atherosclerotic plaques. Myocardial uptake of ¹⁸F-FDG may hamper visualization of the lesions caused by these diseases. Two approaches have been proposed for reducing myocardial uptake in preclinical studies, namely, calcium channel blockers (verapamil) and high-fat diets such as commercial ketogenic diets and sunflower seed diets. The objective of this study was to compare the efficacy of these approaches in reducing myocardial uptake of ¹⁸F-FDG in mice.

Methods

We performed two experiments. In experiment A, each animal underwent four ¹⁸F-FDG PET/CT scans in the following order: baseline, after administration of verapamil, after two days on ketogenic diet and after two days on sunflower seeds. PET scans were performed 60 minutes after injection of 18.5 MBq of ¹⁸F-FDG. In experiment B, the best protocol of the three (ketogenic diet) was evaluated in a lung inflammation model to assess the efficacy of reducing myocardial uptake of ¹⁸F-FDG.

Results

Compared with baseline (SUV 2.03±1.21); the greatest reduction in uptake of ¹⁸F-FDG was with ketogenic diet (SUV 0.79±0.16; p = 0.008), followed by sunflower seeds (SUV 0.91±0.13; p = 0.015); the reduction in myocardial uptake produced by verapamil was not statistically significant (SUV 1.78±0.79; p = NS). In experiment B, complete suppression of myocardial uptake noticeably improved the visualization of inflamed areas near the heart, while in the case of null or partial myocardial suppression, it was much harder to distinguish lung inflammation from myocardial spillover.

Conclusion

A high-fat diet appeared to be the most effective method for decreasing myocardial uptake of ¹⁸F-FDG in healthy mice, outperforming verapamil. Our findings also demonstrate that ketogenic diet actually improves visualization of inflammatory lesions near the heart.     

Inhibition of Platelet Activation and Thrombus Formation by Adenosine and Inosine: Studies on Their Relative Contribution and Molecular Modeling

Background

The inhibitory effect of adenosine on platelet aggregation is abrogated after the addition of adenosine-deaminase. Inosine is a naturally occurring nucleoside degraded from adenosine.

Objectives

The mechanisms of antiplatelet action of adenosine and inosine in vitro and in vivo, and their differential biological effects by molecular modeling were investigated.

Results

Adenosine (0.5, 1 and 2 mmol/L) inhibited phosphatidylserine exposure from 52±4% in the control group to 44±4 (p<0.05), 29±2 (p<0.01) and 20±3% (p<0.001). P-selectin expression in the presence of adenosine 0.5, 1 and 2 mmol/L was inhibited from 32±4 to 27±2 (p<0.05), 14±3 (p<0.01) and 9±3% (p<0.001), respectively. At the concentrations tested, only inosine to 4 mmol/L had effect on platelet P-selectin expression (p<0.05). Adenosine and inosine inhibited platelet aggregation and ATP release stimulated by ADP and collagen. Adenosine and inosine reduced collagen-induced platelet adhesion and aggregate formation under flow. At the same concentrations adenosine inhibited platelet aggregation, decreased the levels of sCD40L and increased intraplatelet cAMP. In addition, SQ22536 (an adenylate cyclase inhibitor) and ZM241385 (a potent adenosine receptor A_2A antagonist) attenuated the effect of adenosine on platelet aggregation induced by ADP and intraplatelet level of cAMP. Adenosine and inosine significantly inhibited thrombosis formation in vivo (62±2% occlusion at 60 min [n = 6, p<0.01] and 72±1.9% occlusion at 60 min, [n = 6, p<0.05], respectively) compared with the control (98±2% occlusion at 60 min, n = 6). A_2A is the adenosine receptor present in platelets; it is known that inosine is not an A_2A ligand. Docking of adenosine and inosine inside A_2A showed that the main difference is the formation by adenosine of an additional hydrogen bond between the NH₂ of the adenine group and the residues Asn253 in H6 and Glu169 in EL2 of the A_2A receptor.

Conclusion

Therefore, adenosine and inosine may represent novel agents lowering the risk of arterial thrombosis.     

Respiratory Motion Reduction in PET/CT Using Abdominal Compression for Lung Cancer Patients

Purpose

Respiratory motion causes substantial artifacts in reconstructed PET images when using helical CT as the attenuation map in PET/CT imaging. In this study, we aimed to reduce the respiratory artifacts in PET/CT images of patients with lung tumors using an abdominal compression device.

Methods

Twelve patients with lung cancer located in the middle or lower lobe of the lung were recruited. The patients were injected with 370 MBq of ¹⁸F-FDG. During PET, the patients assumed two bed positions for 1.5 min/bed. After conducting free-breathing imaging, we obtained images of the patients with abdominal compression by applying the same setup used in the free-breathing scan. The differences in the standardized uptake value (SUV)_max, SUV_mean, tumor volume, and the centroid of the tumors between PET and various CT schemes were measured.

Results

The SUV_max and SUV_mean derived from PET/CT imaging using an abdominal compression device increased for all the lesions, compared with those obtained using the conventional approach. The percentage increases were 18.1% ±14% and 17% ±16.8% for SUV_max and SUV_mean, respectively. PET/CT imaging combined with abdominal compression generally reduced the tumor mismatch between CT and the corresponding attenuation corrected PET images, with an average decrease of 1.9±1.7 mm over all the cases.

Conclusions

PET/CT imaging combined with abdominal compression reduces respiratory artifacts and PET/CT misregistration, and enhances quantitative SUV in tumor. Abdominal compression is easy to set up and is an effective method used in PET/CT imaging for clinical oncology, especially in the thoracic region.     

MRI Evidence for Altered Venous Drainage and Intracranial Compliance in Mild Traumatic Brain Injury

Purpose

To compare venous drainage patterns and associated intracranial hydrodynamics between subjects who experienced mild traumatic brain injury (mTBI) and age- and gender-matched controls.

Methods

Thirty adult subjects (15 with mTBI and 15 age- and gender-matched controls) were investigated using a 3T MR scanner. Time since trauma was 0.5 to 29 years (mean 11.4 years). A 2D-time-of-flight MR-venography of the upper neck was performed to visualize the cervical venous vasculature. Cerebral venous drainage through primary and secondary channels, and intracranial compliance index and pressure were derived using cine-phase contrast imaging of the cerebral arterial inflow, venous outflow, and the craniospinal CSF flow. The intracranial compliance index is the defined as the ratio of maximal intracranial volume and pressure changes during the cardiac cycle. MR estimated ICP was then obtained through the inverse relationship between compliance and ICP.

Results

Compared to the controls, subjects with mTBI demonstrated a significantly smaller percentage of venous outflow through internal jugular veins (60.9±21% vs. controls: 76.8±10%; p = 0.01) compensated by an increased drainage through secondary veins (12.3±10.9% vs. 5.5±3.3%; p<0.03). Mean intracranial compliance index was significantly lower in the mTBI cohort (5.8±1.4 vs. controls 8.4±1.9; p<0.0007). Consequently, MR estimate of intracranial pressure was significantly higher in the mTBI cohort (12.5±2.9 mmHg vs. 8.8±2.0 mmHg; p<0.0007).

Conclusions

mTBI is associated with increased venous drainage through secondary pathways. This reflects higher outflow impedance, which may explain the finding of reduced intracranial compliance. These results suggest that hemodynamic and hydrodynamic changes following mTBI persist even in the absence of clinical symptoms and abnormal findings in conventional MR imaging.     

Effects of a Seven Day Overload-Period of High-Intensity Training on Performance and Physiology of Competitive Cyclists

Objectives

Competitive endurance athletes commonly undertake periods of overload training in the weeks prior to major competitions. This investigation examined the effects of two seven-day high-intensity overload training regimes (HIT) on performance and physiological characteristics of competitive cyclists.

Design

The study was a matched groups, controlled trial.

Methods

Twenty-eight male cyclists (mean ± SD, Age: 33±10 years, Mass 74±7 kg, VO₂ peak 4.7±0.5 L·min⁻¹) were assigned to a control group or one of two training groups for seven consecutive days of HIT. Before and after training cyclists completed an ergometer based incremental exercise test and a 20-km time-trial. The HIT sessions were ∼120 minutes in duration and consisted of matched volumes of 5, 10 and 20 second (short) or 15, 30 and 45 second (long) maximal intensity efforts.

Results

Both the short and long HIT regimes led to significant (p<0.05) gains in time trial performance compared to the control group. Relative to the control group, the mean changes (±90% confidence limits) in time-trial power were 8.2%±3.8% and 10.4%±4.3% for the short and long HIT regimes respectively; corresponding increases in peak power in the incremental test were 5.5%±2.7% and 9.5%±2.5%. Both HIT (short vs long) interventions led to non-significant (p>0.05) increases (mean ± SD) in VO₂ peak (2.3%±4.7% vs 3.5%±6.2%), lactate threshold power (3.6%±3.5% vs 2.9%±5.3%) and gross efficiency (3.2%±2.4% vs 5.1%±3.9%) with only small differences between HIT regimes.

Conclusions

Seven days of overload HIT induces substantial enhancements in time-trial performance despite non-significant increases in physiological measures with competitive cyclists.     

Reducing the Intensity and Volume of Interval Training Diminishes Cardiovascular Adaptation but Not Mitochondrial Biogenesis in Overweight/Obese Men

Objective

The purpose of this research was to determine if the adaptations to high intensity interval training (HIT) are mitigated when both intensity and training volume (i.e. exercise energy expenditure) are reduced.

Methods

19 overweight/obese, sedentary males (Age: 22.7±3.9 yrs, Body Mass Index: 31.4±2.6 kg/m², Waist Circumference: 106.5±6.6 cm) performed 9 sessions of interval training using a 1-min on, 1-min off protocol on a cycle ergometer over three weeks at either 70% (LO) or 100% (HI) peak work rate.

Results

Cytochrome oxidase I protein content, cytochrome oxidase IV protein content, and citrate synthase maximal activity all demonstrated similar increases between groups with a significant effect of training for each. β-hydroxyacyl-CoA dehydrogenase maximal activity tended to increase with training but did not reach statistical significance (p = 0.07). Peroxisome proliferator-activated receptor gamma coactivator-1α and silent mating type information regulator 2 homolog 1 protein contents also increased significantly (p = 0.047), while AMP-activated protein kinase protein content decreased following the intervention (p = 0.019). VO₂peak increased by 11.0±7.4% and 27.7±4.4% in the LO and HI groups respectively with significant effects of both training (p<0.001) and interaction (p = 0.027). Exercise performance improved by 8.6±7.6% in the LO group and 14.1±4.3% in the HI group with a significant effect of training and a significant difference in the improvement between groups. There were no differences in perceived enjoyment or self-efficacy between groups despite significantly lower affect scores during training in the HI group.

Conclusions

While improvements in aerobic capacity and exercise performance were different between groups, changes in oxidative capacity were similar despite reductions in both training intensity and volume.     

Brain MRI CO2 Stress Testing: A Pilot Study in Patients with Concussion

Background

There is a real need for quantifiable neuro-imaging biomarkers in concussion. Here we outline a brain BOLD-MRI CO₂ stress test to assess the condition.

Methods

This study was approved by the REB at the University of Manitoba. A group of volunteers without prior concussion were compared to post-concussion syndrome (PCS) patients – both symptomatic and recovered asymptomatic. Five 3-minute periods of BOLD imaging at 3.0 T were studied – baseline 1 (BL1– at basal CO₂ tension), hypocapnia (CO₂ decreased ∼5 mmHg), BL2, hypercapnia (CO₂ increased ∼10 mmHg) and BL3. Data were processed using statistical parametric mapping (SPM) for 1^st level analysis to compare each subject’s response to the CO₂ stress at the p = 0.001 level. A 2^nd level analysis compared each PCS patient’s response to the mean response of the control subjects at the p = 0.05 level.

Results

We report on 5 control subjects, 8 symptomatic and 4 asymptomatic PCS patients. Both increased and decreased response to CO₂ was seen in all PCS patients in the 2^nd level analysis. The responses were quantified as reactive voxel counts: whole brain voxel counts (2.0±1.6%, p = 0.012 for symptomatic patients for CO₂ response < controls and 3.0±5.1%, p = 0.139 for CO₂ response > controls: 0.49±0.31%, p = 0.053 for asymptomatic patients for CO₂ response < controls and 4.4±6.8%, p = 0.281 for CO₂ response > controls).

Conclusions

Quantifiable alterations in regional cerebrovascular responsiveness are present in concussion patients during provocative CO₂ challenge and BOLD MRI and not in healthy controls. Future longitudinal studies must aim to clarify the relationship between CO₂ responsiveness and individual patient symptoms and outcomes.     

A Non Invasive Estimate of Dead Space Ventilation from Exercise Measurements

Rationale

During exercise, heart failure patients (HF) show an out-of-proportion ventilation increase, which in patients with COPD is blunted. When HF and COPD coexist, the ventilatory response to exercise is unpredictable.

Objectives

We evaluated a human model of respiratory impairment in 10 COPD-free HF patients and in 10 healthy subjects, tested with a progressive workload exercise with different added dead space. We hypothesized that increased serial dead space upshifts the VE vs. VCO₂ relationship and that the VE-axis intercept might be an index of dead space ventilation.

Measurements

All participants performed a cardiopulmonary exercise test with 0, 250 and 500 mL of additional dead space. Since DS does not contribute to gas exchange, ventilation relative to dead space is ventilation at VCO₂ = 0, i.e. VE-axis intercept. We compared dead space volume, estimated dividing VE-axis intercept by the intercept on respiratory rate axis of the respiratory rate vs. VCO₂ relationship with standard method measured DS.

Main results

In HF, adding dead space increased VE-axis intercept (+0 mL = 4.98±1.63 L; +250 mL = 9.69±2.91 L; +500 mL = 13.26±3.18 L; p<0.001) and upshifted the VE vs.VCO₂ relationship, with a minor slope rise (+0 mL = 27±4 L; +250 = 28±5; +500 = 29±4; p<0.05). In healthy, adding dead space increased VE-axis intercept (+0 mL = 4.9±1.4 L; +250 = 9.3±2.4; +500 = 13.1±3.04; p<0.001) without slope changes. Measured and estimated dead space volumes were similar both in HF and healthy subjects.

Conclusions

VE-axis intercept is related to dead space ventilation and dead space volume can be non-invasively estimated.     

A Semi-Automated Technique Determining the Liver Standardized Uptake Value Reference for Tumor Delineation in FDG PET-CT

Background

¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) has been an essential modality in oncology. We propose a semi-automated algorithm to objectively determine liver standardized uptake value (SUV), which is used as a threshold for tumor delineation.

Methods

A large spherical volume of interest (VOI) was placed manually to roughly enclose the right lobe (RL) of the liver. For each voxel in this VOI, a coefficient of variation of voxel values (CVv) was calculated for neighboring voxels within a radius of d/2. The voxel with the minimum CVv was then selected, where a 30-mm spherical VOI was placed at that voxel in accordance with PERCIST criteria. Two nuclear medicine physicians independently defined 30-mm VOIs manually on 124 studies in 62 patients to generate the standard values, against which the results from the new method were compared.

Results

The semi-automated method was successful in determining the liver SUV that was consistent between the two physicians in all the studies (d = 80 mm). The liver SUV threshold (mean +3 SD within 30-mm VOI) determined by the new semi-automated method (3.12±0.61) was not statistically different from those determined by the manual method (Physician-1: 3.14±0.58, Physician-2: 3.15±0.58). The semi-automated method produced tumor volumes that were not statistically different from those by experts'' manual operation. Furthermore, the volume change in the two sequential studies had no statistical difference between semi-automated and manual methods.

Conclusions

Our semi-automated method could define the liver SUV robustly as the threshold value used for tumor volume measurements according to PERCIST. The method could avoid possible subjective bias of manual liver VOI placement and is thus expected to improve clinical performance of volume-based parameters for prediction of cancer treatment response.     

Role of Alveolar β2-Adrenergic Receptors on Lung Fluid Clearance and Exercise Ventilation in Healthy Humans

Background

In experimental conditions alveolar fluid clearance is controlled by alveolar β₂-adrenergic receptors. We hypothesized that if this occurs in humans, then non-selective β-blockers should reduce the membrane diffusing capacity (D_M), an index of lung interstitial fluid homeostasis. Moreover, we wondered whether this effect is potentiated by saline solution infusion, an intervention expected to cause interstitial lung edema. Since fluid retention within the lungs might trigger excessive ventilation during exercise, we also hypothesized that after the β₂-blockade ventilation increased in excess to CO₂ output and this was further enhanced by interstitial edema.

Methods and Results

22 healthy males took part in the study. On day 1, spirometry, lung diffusion for carbon monoxide (DLCO) including its subcomponents D_M and capillary volume (V_Cap), and cardiopulmonary exercise test were performed. On day 2, these tests were repeated after rapid 25 ml/kg saline infusion. Then, in random order 11 subjects were assigned to oral treatment with Carvedilol (CARV) and 11 to Bisoprolol (BISOPR). When heart rate fell at least by 10 beats·min⁻¹, the tests were repeated before (day 3) and after saline infusion (day 4). CARV but not BISOPR, decreased D_M (−13±7%, p = 0.001) and increased V_Cap (+20±22%, p = 0.016) and VE/VCO₂ slope (+12±8%, p<0.01). These changes further increased after saline: −18±13% for D_M (p<0.01), +44±28% for V_Cap (p<0.001), and +20±10% for VE/VCO₂ slope (p<0.001).

Conclusions

These findings support the hypothesis that in humans in vivo the β₂-alveolar receptors contribute to control alveolar fluid clearance and that interstitial lung fluid may trigger exercise hyperventilation.