Baseline Blood Volume Research Articles

Contrast-enhanced ultrasound imaging detects anatomical and functional changes in rat cervical spine microvasculature with normal aging.

Normal aging is associated with significant deleterious cerebrovascular changes; these have been implicated in disease pathogenesis and increased susceptibility to ischemic injury. While these changes are well documented in the brain, few studies have been conducted in the spinal cord. Here, we utilize specialized contrast-enhanced ultrasound (CEUS) imaging to investigate age-related changes in cervical spinal vascular anatomy and hemodynamics in male Fisher 344 rats, a common strain in aging research. Aged rats (24-26 mo., N=6) exhibited significant tortuosity in the anterior spinal artery and elevated vascular resistance compared to adults (4-6 mo., N=6; tortuosity index 2.20±0.15 vs 4.74±0.45, p<0.05). Baseline blood volume was lower in both larger vessels and the microcirculation in the aged cohort, specifically in white matter (4.44e14±1.37e13 vs 3.66e14±2.64e13 CEUS bolus AUC, p<0.05). To elucidate functional differences, animals were exposed to a hypoxia challenge; whereas adult rats exhibited significant functional hyperemia in both gray and white matter (GM: 1.13±0.10-fold change from normoxia, p<0.05; WM: 1.16±0.13, p<0.05), aged rats showed no response. Immunohistochemistry revealed reduced pericyte coverage and activated microglia behavior in aged rats, which may partially explain the lack of vascular response. This study provides the first in vivo description of age-related hemodynamic differences in the cervical spinal cord.

DCE-CT parameters as new functional imaging biomarkers at baseline and during immune checkpoint inhibitor therapy in patients with lung cancer – a feasibility study

BackgroundWith the development of immune checkpoint inhibitors for the treatment of non-small cell lung cancer, the need for new functional imaging techniques and early response assessments has increased to account for new response patterns and the high cost of treatment. The present study was designed to assess the prognostic impact of dynamic contrast-enhanced computed tomography (DCE-CT) on survival outcomes in non-small cell lung cancer patients treated with immune checkpoint inhibitors.MethodsThirty-three patients with inoperable non-small-cell lung cancer treated with immune checkpoint inhibitors were prospectively enrolled for DCE-CT as part of their follow-up. A single target lesion at baseline and subsequent follow-up examinations were enclosed in the DCE-CT. Blood volume deconvolution (BVdecon), blood flow deconvolution (BFdecon), blood flow maximum slope (BFMax slope) and permeability were assessed using overall survival (OS) and progression-free survival (PFS) as endpoints in Kaplan Meier and Cox regression analyses.ResultsHigh baseline Blood Volume (BVdecon) (> 12.97 ml × 100 g−1) was associated with a favorable OS (26.7 vs 7.9 months; p = 0.050) and PFS (14.6 vs 2.5 months; p = 0.050). At early follow-up on day seven a higher relative increase in BFdecon (> 24.50% for OS and > 12.04% for PFS) was associated with an unfavorable OS (8.7 months vs 23.1 months; p < 0.025) and PFS (2.5 vs 13.7 months; p < 0.018). The relative change in BFdecon (categorical) on day seven was a predictor of OS (HR 0.26, CI95: 0.06 to 0.93 p = 0.039) and PFS (HR 0.27, CI95: 0.09 to 0.85 p = 0.026).ConclusionDCE-CT-identified parameters may serve as potential prognostic biomarkers at baseline and during early treatment in patients with NSCLC treated with immune checkpoint inhibitor therapy.

Human whole-brain models of cerebral blood flow and oxygen transport

The cerebral vasculature plays a critical role in the transport of oxygen and other nutrients to brain tissue. However, the size, complexity, and paucity of detailed anatomical information of this system makes understanding cerebral behaviour in normal and pathological conditions, as well as its response to stimuli, highly challenging. Whole-brain mathematical models have a valuable role to play in the understanding and measurement of cerebral parameters. However, for the same reasons, whole-brain models are highly complex to construct. In this study, we propose a novel multi-compartment approach to blood flow and oxygen transport. Building on prior models, we propose a new formulation based on a multiple compartment porous medium approach. Using non-dimensional analysis, we derive the most compact form of the equations and constrain the parameter space using clinically measurable quantities, such as baseline perfusion and blood volume. We illustrate the spatially and temporally varying response of the brain by simulating the response to changes in both arterial blood pressure and arterial oxygen saturation, showing that the oxygen response is strongly dependent upon depth, with large but slow responses being found deep in the brain and small but fast responses nearer the surface, whereas the flow response is very rapid in comparison. Blood flow and oxygenation are thus shown to exhibit very different characteristic time scales. This has significant implications for how we consider the response of the brain to external stimuli, such the autoregulation and reactivity responses, and how we model the brain at different time scales.Statement of Significance: In this study we present a new mathematical model for simulations of blood flow and oxygen transport in the human brain. A compact representation is obtained from analysis of the governing equations and different time scales are identified. We show that the behaviour is strongly depth dependent and that 3D models exhibit very different behaviour from simplified 1D models. This will be important in developing further models of the brain, particularly in simulating its active response.

Serial blood volume measurements in patients with compensated chronic heart failure: How do volume profiles change over time?

Among patients with chronic heart failure (HF) intravascular volume profiles vary significantly despite similar clinical compensation. However, little is known regarding changes in blood volume (BV) profiles over time. The objective of this analysis was to identify the extent and character of changes in volume profiles over time. A prospective analysis was undertaken in patients who were hospitalized and treated for fluid overload. Quantitative BV analyses were obtained in a compensated state at hospital discharge (baseline) and follow-up at 1, 3, and 6 mo. Data were available on 10 patients who remained stable without rehospitalization or medication change over a 6-mo period. Baseline BV profiles were highly variable at hospital discharge with an average deviation of +28% above normal in 6 patients and normal BV in 4 patients. Over the follow-up period, the median change in BV was -201 mL [-3% (-6, +3%)] from baseline with profiles remaining in the same volume category in 9 out of 10 patients. Crossover from normal BV to mild contraction (-13% of normal) occurred in one patient. Red blood cell mass demonstrated the largest change over 6 mo [median -275 (-410, +175) mL] with a deviation from normal of -14 (-20, +8) % (reflecting mild anemia). These findings suggest that BV profiles in clinically compensated patients with HF do not change substantially over a 6-mo period regardless of baseline expanded or normal BV. This lack of change in volume profiles particularly from an expanded BV has implications for long-term volume management, clinical outcomes, and also our understanding of volume homeostasis in HF.NEW & NOTEWORTHY The novel findings of this study demonstrate that blood volume profiles while highly variable in clinically compensated patients with HF on stable medical therapy do not change substantially over a 6-mo period regardless of baseline expanded or normal blood volumes. This lack of change in volume profiles particularly from an expanded blood volume has implications for long-term volume management and also for how we understand the pathophysiology of volume homeostasis in chronic HF.

Correspondence between BOLD fMRI task response and cerebrovascular reactivity across the cerebral cortex.

BOLD sensitivity to baseline perfusion and blood volume is a well-acknowledged fMRI confound. Vascular correction techniques based on cerebrovascular reactivity (CVR) might reduce variance due to baseline cerebral blood volume, however this is predicated on an invariant linear relationship between CVR and BOLD signal magnitude. Cognitive paradigms have relatively low signal, high variance and involve spatially heterogenous cortical regions; it is therefore unclear whether the BOLD response magnitude to complex paradigms can be predicted by CVR. The feasibility of predicting BOLD signal magnitude from CVR was explored in the present work across two experiments using different CVR approaches. The first utilized a large database containing breath-hold BOLD responses and 3 different cognitive tasks. The second experiment, in an independent sample, calculated CVR using the delivery of a fixed concentration of carbon dioxide and a different cognitive task. An atlas-based regression approach was implemented for both experiments to evaluate the shared variance between task-invoked BOLD responses and CVR across the cerebral cortex. Both experiments found significant relationships between CVR and task-based BOLD magnitude, with activation in the right cuneus (R 2 = 0.64) and paracentral gyrus (R 2 = 0.71), and the left pars opercularis (R 2 = 0.67), superior frontal gyrus (R 2 = 0.62) and inferior parietal cortex (R 2 = 0.63) strongly predicted by CVR. The parietal regions bilaterally were highly consistent, with linear regressions significant in these regions for all four tasks. Group analyses showed that CVR correction increased BOLD sensitivity. Overall, this work suggests that BOLD signal response magnitudes to cognitive tasks are predicted by CVR across different regions of the cerebral cortex, providing support for the use of correction based on baseline vascular physiology.

CT perfusion as a potential biomarker for pancreatic ductal adenocarcinoma during routine staging and restaging.

To evaluate the significance of CT perfusion parameters predicting response to neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma (PDAC). Seventy patients with PDAC prospectively had CT perfusion acquisition incorporated into baseline multiphase staging CT. Twenty-eight who were naïve to therapy were retained for further investigation. Perfusion was performed 5-42.5s after contrast, followed by parenchymal and portal venous phases. Blood flow (BF), blood volume (BV), and permeability surface area product (PS) were calculated using deconvolution algorithms. Patients were categorized as responders or non-responders per RECIST 1.1. Perfusion variables with AUC ≥ 0.70 in differentiating responders from non-responders were retained. Logistic regression was used to assess associations between baseline perfusion variables and response. 18 of 28 patients showed favorable response to therapy. Baseline heterogeneity variables in tumor max ROI were higher in non-responders than responders [median BF coefficient of variation (CV) 0.91 vs. 0.51 respectively, odds ratio (OR) 6.8 per one standard deviation (1-SD) increase, P = 0.047; median PS CV 1.6 vs. 0.68, OR 3.9 per 1-SD increase, P = 0.047; and median BV CV 0.75 vs. 0.54, OR = 4.0 per 1-SD increase, P = 0.047]. Baseline BV mean in tumor center was lower in non-responders than responders (median BV mean: 0.74 vs. 2.9ml/100g respectively, OR 0.28 per 1-SD increase, P = 0.047). For patients with PDAC receiving neoadjuvant therapy, lower and more heterogeneous perfusion parameters correlated with an unfavorable response to therapy. Such quantitative information can be acquired utilizing a comprehensive protocol interleaving perfusion CT acquisition with standard of care multiphase CT scans using a single contrast injection, which could be used to identify surgical candidates and predict outcome.

The neuroprotective effects of oxygen therapy in Alzheimer’s disease: a narrative review

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

Model-informed drug development of voxelotor in sickle cell disease: Population pharmacokinetics in whole blood and plasma.

Oxbryta (voxelotor) is a small‐molecule inhibitor of sickle hemoglobin (Hb) polymerization approved for patients with sickle cell disease (SCD) aged greater than or equal to 12 years at a dose of 1500 mg once daily (q.d.). Voxelotor binds preferentially to Hb, and voxelotor partitioning into red blood cells is an effective predictor of Hb occupancy. The objectives of these analyses were to develop a population pharmacokinetic (PopPK) model for voxelotor in both plasma and whole blood in adults and adolescents to support the dose selection for optimal target engagement and to identify covariates that have a significant effect on voxelotor pharmacokinetics (PK) in plasma and whole blood. An integrated plasma and whole blood PopPK model with two compartments, first‐order absorption and elimination, and a site‐of‐action effect compartment adequately described the concentration‐time profiles of voxelotor in plasma and whole blood in patients treated up to 72 weeks. Covariates with significant effects on voxelotor PK included baseline blood volume on apparent volume of the central compartment and time‐varying hematocrit and dose on whole blood partitioning, indicating that clinical markers of voxelotor effect can, in turn, influence its PK. Furthermore, the model confirmed that voxelotor PK in plasma and whole blood is linear with dose and time and comparable for adults and adolescents. No clinically important covariate effects on voxelotor PK that warranted dose adjustment were identified in this analysis. Overall, the PopPK analyses contributed significantly to the voxelotor label and support 1500 mg q.d. as the therapeutic dose in adults and adolescents with SCD.

A systematic review of risk factors for postinduction hypotension in surgical patients undergoing general anesthesia.

Clinical evidence has proved that postinduction hypotension (PIH) is very prevalent in surgical patients undergoing general anesthesia, and commonly develops within 20 min after the induction of general anesthesia. However, the risk factors for PIH are not clear till now, therefore, a systematic review of current evidence was conducted. PubMed, Embase, Cochrane library, and Web of Science were searched for articles published in English up to June 2021. The following search items were used: postinduction, postintubation, propofol induction, anesthesia induction, general anesthesia induction, hypotension, risk factor, general anesthesia, surgery. The articles were screened using the inclusion and exclusion criteria, and the data from included studies were extracted and analyzed. Twelve studies were included. Seven studies reported the association between age and PIH, and six showed age was a risk factor. Five or three studies reported the association between mean arterial pressure (MAP) and PIH or between systolic blood pressure (SBP) and PIH, but the results were conflicting. Results from two studies regarding gender and PIH were conflicting. Two studies reported that weight was negatively correlated with PIH. Low baseline blood volume, emergency operation, long-term intake of the angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) were risk factors for PIH. One study showed that ASA III-V, propofol induction, and increasing fentanyl dosage were risk factors for PIH. Aging, ASA III-V, emergency operation, low baseline blood volume, long-term intake of ACEI/ARB, propofol induction, and increasing fentanyl dosage are potential risk factors for PIH, while body weight gain is a protective factor. Based on the current evidence, it is difficult to determine whether baseline blood pressure or gender is associated with the development of PIH.

Baseline blood volume identified by dynamic contrast-enhanced computed tomography as a new independent prognostic factor in metastatic renal cell carcinoma.

BackgroundPreliminary data showed prognostic impact of contrast-enhanced computed tomography (DCE-CT) identified Blood Volume (BV) in patients with metastatic renal cell carcinoma (mRCC). BV as an independent prognostic factor remains to be assessed.Materials and MethodsDCE-CT identified BV was prospectively quantified in patients with mRCC receiving first line therapies, adjusted for International mRCC Database Consortium (IMDC) individual features and treatments, and associated with overall survival (OS), progression-free survival (PFS) and objective response (ORR), using Cox and logistic regression, respectively.Results105 patients with mRCC were included. Median baseline BV was 32.87 mL × 100 g−1 (range 9.52 to 92.87 mL × 100 g−1). BV above median was associated with IMDC favorable risk category (P = 0.004), metastasis free interval ≥ 1 year (P = 0.007), male gender (P = 0.032), normal hemoglobin (P = 0.040) and normal neutrophils (P = 0.007), whereas low BV was associated with poor risk IMDC features (P < 0.05). Patients with high vs. low baseline BV had longer PFS (12.5 vs. 5.6 months, P = 0.015) and longer OS (42.2 vs. 22.4 months, P = 0.001), respectively. In multivariate analysis high baseline BV remained independent favorable for OS (HR 0.49, 95% CI 0.30–0.78, P = 0.003) and PFS (HR 0.64; 95% CI 0.42–0.97, P = 0.036). BV as a continuous variable was also associated with OS in the multivariate analysis (HR 0.98, 95% CI 0.96–1.00, P = 0.017). The estimated concordance index (c-index) was 0.688 using IMDC score and 0.701 when BV was added.ConclusionsDCE-CT identified Blood Volume is a new, independent prognostic factor in mRCC, which may improve the prognostic accuracy of IMDC.

Enhanced Cerebral Blood Volume under Normobaric Hyperoxia in the J20-hAPP Mouse Model of Alzheimer\u2019s Disease

Early impairments to neurovascular coupling have been proposed to be a key pathogenic factor in the onset and progression of Alzheimer’s disease (AD). Studies have shown impaired neurovascular function in several mouse models of AD, including the J20-hAPP mouse. In this study, we aimed to investigate early neurovascular changes using wild-type (WT) controls and J20-hAPP mice at 6 months of age, by measuring cerebral haemodynamics and neural activity to physiological sensory stimulations. A thinned cranial window was prepared to allow access to cortical vasculature and imaged using 2D-optical imaging spectroscopy (2D-OIS). After chronic imaging sessions where the skull was intact, a terminal acute imaging session was performed where an electrode was inserted into the brain to record simultaneous neural activity. We found that cerebral haemodynamic changes were significantly enhanced in J20-hAPP mice compared with controls in response to physiological stimulations, potentially due to the significantly higher neural activity (hyperexcitability) seen in the J20-hAPP mice. Thus, neurovascular coupling remained preserved under a chronic imaging preparation. Further, under hyperoxia, the baseline blood volume and saturation of all vascular compartments in the brains of J20-hAPP mice were substantially enhanced compared to WT controls, but this effect disappeared under normoxic conditions. This study highlights novel findings not previously seen in the J20-hAPP mouse model, and may point towards a potential therapeutic strategy.

979P - High baseline blood volume is an independent favorable prognostic factor for overall and progression-free survival in patients with metastatic renal cell carcinoma

BackgroundData on functional imaging parameters such as blood volume (BV) in metastatic renal cell carcinoma (mRCC) is limited. We assessed the association of baseline BV with survival outcome adjusted for baseline clinical factor in patients with mRCC. MethodsBV was quantified using dynamic contrast-enhanced computed tomography in patients from two prospective studies; Angiogenesis Inhibitor Study (AIS) with pazopanib, sunitinib and temsirolimus and the Danish Renal Cancer Group Study-1 (Darenca-1) with interleukin-2, interferon alpha with or without bevacizumab. Data were analyzed using an Advanced Perfusion and Permeability Application softwareprogram, Phillips. BV was evaluated as a binary (above/below median) and as a continuous variable adjusted for treatment, gender, and individual IMDC factors. Association was evaluated using chi squared test for clinical factors, Cox regression for overall survival (OS) and progression-free survival (PFS), and logistic regression for objective response rate (ORR). ResultsAmong 122 included patients, 105 patients had technically feasible scans and were included in the final analysis (AIS, N=29 and Darenca-1, N=76). Median BV was 32.87mL * 100g-1 (range 9.52 to 92.87). BV above median was associated with IMDC favorable risk group (p=0.004), metastasis free interval > 1 year (p=0.007) and male gender (p=0.032). BV below median was associated with anemia (p=0.040) and neutrophilia (p=0.007). Patients with high vs. low baseline BV had longer PFS (12.5 vs. 5.6 months, p=0.015) and longer OS (42.2 vs. 22.4 months, p=0.001), respectively. In multivariate analysis, high baseline BV remained an independent favorable prognostic factor (OS: HR 0.49, 95% CI 0,30-0,78, p=0.003, PFS: HR 0.64; 95% CI 0,42-0,97, p=0.040). BV analyzed as a continuous variable was also associated with OS in multivariate analysis (HR 0.98, 95% CI 0,96-1,00, p=0,017). No association was found between BV and ORR (OR 1.56; 95% CI 0,67-3,63, p=0.3). ConclusionsHigh baseline BV, obtained using functional imaging, is a new independent favorable prognostic factor associated with longer PFS and OS in patients with mRCC. Further research in functional imaging is encouraged. Clinical trial identificationNCT01274273 (Darenca-1 Study). Legal entity responsible for the studyAuthors. FundingPhillips Healthcare provided the software used for DCE-CT analysis Roche and Novartis supported the clinical part of the study financially - but were however not invovled in the imaging analysis. DisclosureA. Drljevic-Nielsen: Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: BMS. F. Donskov: Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Ipsen. All other authors have declared no conflicts of interest.

A dynamical model of the laminar BOLD response

High-resolution functional magnetic resonance imaging (fMRI) using blood oxygenation dependent level-dependent (BOLD) signal is an increasingly popular tool to non-invasively examine neuronal processes at the mesoscopic level. However, as the BOLD signal stems from hemodynamic changes, its temporal and spatial properties do not match those of the underlying neuronal activity. In particular, the laminar BOLD response (LBR), commonly measured with gradient-echo (GE) MRI sequence, is confounded by non-local changes in deoxygenated hemoglobin and cerebral blood volume propagated within intracortical ascending veins, leading to a unidirectional blurring of the neuronal activity distribution towards the cortical surface. Here, we present a new cortical depth-dependent model of the BOLD response based on the principle of mass conservation, which takes the effect of ascending (and pial) veins on the cortical BOLD responses explicitly into account. It can be used to dynamically model cortical depth profiles of the BOLD signal as a function of various baseline- and activity-related physiological parameters for any spatiotemporal distribution of neuronal changes. We demonstrate that the commonly observed spatial increase of LBR is mainly due to baseline blood volume increase towards the surface. In contrast, an occasionally observed local maximum in the LBR (i.e. the so-called “bump”) is mainly due to spatially inhomogeneous neuronal changes rather than locally higher baseline blood volume. In addition, we show that the GE-BOLD signal laminar point-spread functions, representing the signal leakage towards the surface, depend on several physiological parameters and on the level of neuronal activity. Furthermore, even in the case of simultaneous neuronal changes at each depth, inter-laminar delays of LBR transients are present due to the ascending vein. In summary, the model provides a conceptual framework for the biophysical interpretation of common experimental observations in high-resolution fMRI data. In the future, the model will allow for deconvolution of the spatiotemporal hemodynamic bias of the LBR and provide an estimate of the underlying laminar excitatory and inhibitory neuronal activity.

Dynamic Contrast-Enhanced Computed Tomography-Derived Blood Volume and Blood Flow Correlate With Patient Outcome in Metastatic Renal Cell Carcinoma.

The aim was to explore the potential for using dynamic contrast-enhanced computed tomography as a noninvasive functional imaging biomarker before and during the early treatment of metastatic renal cell carcinoma (mRCC). Dynamic contrast-enhanced computed tomography scans were performed at baseline and after 5 and 10 weeks' treatment in 69 prospectively included mRCC patients receiving treatment with interferon alpha and interleukin 2 (n = 26); interferon alpha, interleukin 2, and bevacizumab (n = 24); sunitinib (n = 7); pazopanib (n = 5); or temsirolimus (n = 7). Using a prototype software program (Advanced Perfusion and Permeability Application, Philips Healthcare, Best, the Netherlands), blood volume (BV), blood flow (BF), and permeability surface area product (PS) were calculated for each tumor at baseline, week 5, and week 10. These parameters as well as relative changes between baseline and weeks 5 and 10 were tested for associations with progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier curves and log-rank tests. Using the 25th percentile as the cutoff, baseline BV for all patients independent of subsequent treatment was statistically significantly associated with PFS (10.8 vs 5.3 months, P = 0.007) and OS (35.2 vs 13.3 months, P = 0.001), and baseline BF was significantly associated with OS (31.7 vs 14.6 months, P = 0.024) with high values for both parameters being associated with significantly longer PFS and OS. Baseline PS was not associated with PFS or OS.In patients treated with angiogenesis inhibitors (bevacizumab, sunitinib, pazopanib, or temsirolimus), the relative change in BV from baseline to week 5 using 25th percentile as the cutoff was associated with PFS (5.6 vs 24.8 months, P = 0.001) and OS (19.1 months vs not reached, P = 0.008) and from baseline to week 10 with PFS (8.1 vs 16.4 months, P = 0.014) and OS (15.5 months vs not reached, P = 0.002). The relative change in BF from baseline to week 5 using medians as the cutoff was associated with PFS (5.5 vs 14.3 months, P = 0.018) and OS (14.6 vs 31.7 months, P = 0.027). The relative change in BF from baseline to week 10 using 25th percentile as the cutoff was associated with PFS (8.3 vs 46.9 months, P = 0.011) and OS (19.1 vs 53.0 months, P = 0.006). For both parameters, the largest reductions during early treatment were associated with increased PFS and OS.In patients receiving immunotherapy only (interferon alpha and interleukin 2), relative changes in PS between baseline and weeks 5 and 10 were significantly associated with PFS with larger increases associated with longer PFS. In patients receiving angiogenesis inhibitors, the relative changes in PS between baseline and week 10 were significantly associated with PFS and OS with larger reductions associated with favorable outcomes. In patients with mRCC treated with angiogenesis inhibitors, the largest reductions in BV and BF between baseline and weeks 5 and 10 were associated with favorable outcomes. At baseline, the lowest BV and BF were associated with the poorest outcomes regardless of the subsequent treatment. Early reductions in PS were associated with favorable outcomes for those treated with angiogenesis inhibitors and with poor outcomes for those treated with immunotherapies.

Caffeine Does Not Reduce Blood Flow Following Arterial Anastomosis in the Rat.

Background Patients are usually advised not to consume caffeine following digital replantation. This study examined the effect of caffeine on blood flow distal to the site of anastomosis in the femoral arteries of rats. Methods A total of 28 Sprague-Dawley rats were used for this study. The femoral arteries were exposed bilaterally and baseline blood volume flow measurements were taken on intact arteries using a transit time flow-meter probe. All rats underwent transection and microvascular anastomosis of the femoral artery on the right side while the left side remained intact to serve as a control. The rats were then divided into two groups. In group 1, caffeine was administered (intraperitoneal injection of 40 mg caffeine/kg of body weight dissolved in saline) and in group 2 no caffeine was given. In both the groups, bilateral flow measurements were then taken at 30 and 60 minutes, respectively, following completion of the anastomosis. Results All anastomoses remained patent during the study time period. Caffeine had no statistical effect on blood flow distal to the anastomosis. Both anastomosed and control arteries demonstrated a statistically significant increase in blood flow at 30 and 60 minutes, respectively, postanastomosis that was independent of caffeine administration. Conclusions Caffeine does not have a statistically significant effect on blood flow distal to the anastomosis following microsurgical repair of the rat femoral artery.

Investigating the impact of passive external lower limb compression on central and peripheral hemodynamics during exercise.

The objective of this study was to assess the effectiveness of graduated compression socks (GCS) on enhancing muscle blood flow and oxygenation during exercise and recovery in healthy subjects. Twelve healthy volunteers completed a protocol involving baseline, exercise, and recovery periods with and without GCS. Each test was repeated twice to assess repeatability of the results. The applied sock pressure was measured prior to experimentation using a custom pressure sensing system, and modified as necessary using tensor bandages to control the applied load. During each of the experimental phases, blood velocity in the popliteal artery, calf muscle tissue oxygenation, muscle activity, heart rate, blood pressure, cardiac output, and applied pressure from the sock were measured. Popliteal artery diameter was measured during baseline and recovery periods. The GCS significantly reduced deoxyhemoglobin (HHb) in the leg during baseline (HHb, p = 0.001) and total blood volume and HHb in the leg during exercise (total hemoglobin, p = 0.01; HHb, p = 0.02). However, there were no differences in leg muscle blood flow velocity or any other variables with and without GCS at baseline, exercise, or recovery. Interestingly, it was found that the local applied sock pressure was very sensitive to the sock application process and, furthermore, the pressure varied considerably during exercise. No significant changes were observed in measures reflecting oxygen delivery for healthy subjects using GCS during exercise and recovery. Applied sock pressure was carefully controlled, thus eliminating the sock application process as a variable.

Rapid Weight Loss and the Body Fluid Balance and Hemoglobin Mass of Elite Amateur Boxers

Dehydration is assumed to be a major adverse effect associated with rapid loss of body mass for competing in a lower weight class in combat sports. However, the effects of such weight cutting on body fluid balance in a real-life setting are unknown. To examine the effects of 5% or greater loss of body mass within a few days before competition on body water, blood volume, and plasma volume in elite amateur boxers. Case-control study. Sports medicine laboratory. Seventeen male boxers (age = 19.2 ± 2.9 years, height = 175.1 ± 7.0 cm, mass = 65.6 ± 9.2 kg) were assigned to the weight-loss group (WLG; n = 10) or the control group (CON; n = 7). The WLG reduced body mass by restricting fluid and food and inducing excessive sweat loss by adhering to individual methods. The CON participated in their usual precompetition training. During an ordinary training period (t-1), 2 days before competition (t-2), and 1 week after competition (t-3), we performed bioelectrical impedance measurements; calculated total body water, intracellular water, and extracellular water; and estimated total hemoglobin mass (tHbmass), blood volume, and plasma volume by the CO-rebreathing method. In the WLG, the loss of body mass (5.6% ± 1.7%) led to decreases in total body water (6.0% ± 0.9%), extracellular water (12.4% ± 7.6%), tHbmass (5.3% ± 3.8%), blood volume (7.6% ± 2.1%; P < .001), and plasma volume (8.6% ± 3.9%). The intracellular water did not change (P > .05). At t-3, total body water, extracellular water, and plasma volume had returned to near baseline values, but tHbmass and blood volume still were less than baseline values (P < .05). In CON, we found no changes (P > .05). In a real-life setting, the loss of approximately 6% body mass within 5 days induced hypohydration, which became evident by the decreases in body water and plasma volume. The reduction in tHbmass was a surprising observation that needs further investigation.

Spatiotemporal characteristics and vascular sources of neural-specific and -nonspecific fMRI signals at submillimeter columnar resolution

The neural specificity of hemodynamic-based functional magnetic resonance imaging (fMRI) signals is dependent on both the vascular regulation and the sensitivity of the applied fMRI technique to different types and sizes of blood vessels. In order to examine the specificity of MRI-detectable hemodynamic responses, submillimeter blood oxygenation level-dependent (BOLD) and cerebral blood volume (CBV) fMRI studies were performed in a well-established cat orientation column model at 9.4 T. Neural-nonspecific and -specific signals were separated by comparing the fMRI responses of orthogonal orientation stimuli. The BOLD response was dominantly neural-nonspecific, mostly originating from pial and intracortical emerging veins, and thus was highly correlated with baseline blood volume. Uneven baseline CBV may displace or distort small functional domains in high-resolution BOLD maps. The CBV response in the parenchyma exhibited dual spatiotemporal characteristics, a fast and early neural-nonspecific response (with 4.3-s time constant) and a slightly slower and delayed neural-specific response (with 9.4-s time constant). The nonspecific CBV signal originates from early-responding arteries and arterioles, while the specific CBV response, which is not correlated with baseline blood volume, arises from late-responding microvessels including small pre-capillary arterioles and capillaries. Our data indicate that although the neural specificity of CBV fMRI signals is dependent on stimulation duration, high-resolution functional maps can be obtained from steady-state CBV studies.

Predicting response to neoadjuvant chemotherapy in primary breast cancer using volumetric helical perfusion computed tomography: a preliminary study

To investigate whether CT-derived vascular parameters in primary breast cancer predict complete pathological response (pCR) to neoadjuvant chemotherapy (NAC). Twenty prospective patients with primary breast cancer due for NAC underwent volumetric helical perfusion CT to derive whole tumour regional blood flow (BF), blood volume (BV) and flow extraction product (FE) by deconvolution analysis. A pCR was achieved if no residual invasive cancer was detectable on pathological examination. Relationships between baseline BF, BV, FE, tumour size and volume, and pCR were examined using the Mann-Whitney U test. Receiver operating characteristic (ROC) curve analysis was performed to assess the parameter best able to predict response. Intra- and inter-observer variability was assessed using Bland-Altman statistics. Seventeen out of 20 patients completed NAC with four achieving a pCR. Baseline BF and FE were higher in patients who achieved a pCR compared with those who did not (P = 0.032); tumour size and volume were not significantly different (P > 0.05). ROC analysis revealed that BF and FE were able to identify responders effectively (AUC = 0.87; P = 0.03). There was good intra- and inter-observer agreement. Primary breast cancers which exhibited higher levels of perfusion before treatment were more likely to achieve a pCR to NAC.

Abstract 1317: Dose-dependent effects of bevacizumab on human HCC xenografts

Abstract Introduction: Bevacizumab has demonstrated positive clinical treatment effect and is currently approved for treatment of colorectal carcinoma and NSCLC in combination with standard chemotherapy. Preclinical studies have shown decrease in microvascular density. We aim to determine if DCE-MRI is a sensitive enough technique to detect changes in fractional intravascular volume after administration of a single dose of bevacizumab. Materials and Methods: Mice: Twenty-seven male BALB/c mice (6 weeks old, 24 ± 2g) formed the study population &amp; were under 1-2 % isoflurane during the scanning. They were implanted with human-derived HCC xenograft line, sensitive to bevacizumab therapy. Two dose levels were investigated: low dose (n = 4) at 1 mg/kg and high dose (n=8) at 10 mg/kg. Mice were scanned at baseline, day 1 and 5 after therapy. Fifteen control mice were similarly imaged after receiving omalizumab, a human anti-IgE antibody, at 10 mg/kg. Tumors were sectioned and stained immunohistochemically to identify CD34 for quantification of MVD. DCE-MRI: MRI was performed on a 7T scanner (Bruker ClinScan, Bruker BioSpin MRI GmbH, Germany). A 3D VIBE sequence was used with following parameters: TR = 3.04 ms, TE = 1.23 ms, FOV = 36 × 36 mm, 128 × 128 matrix, 8 slices with thickness of 1 mm, &amp; temporal resolution 2 s. Five sets of baseline images were acquired with ≤ = 6° &amp; 14°. It was followed by a dynamic sequence of 130 sets of images (α = 14°). A dose of 100 µL of Gd-DOTA (Dotarem, Guerbet SA, France) at 1 mmol/kg was injected through the tail vein after the first set of dynamic images. Data Processing: Region of interests corresponding to the xenograft and major artery were manually outlined. Blood volume was derived from the standard two-compartment model. Results: Baseline blood volume for the control group was 7.32 ± 3.47 %. The values were 9.67 ± 1.72 % for the group treated with bevacizumab 1 mg/kg and 10.02 ± 3.85 % for the group dosed with bevacizumab 10 mg/kg. A reduction of 52.69 ± 24.77 % in blood volume at Day 1 and 75.25 ± 12.58 % at Day 5 was observed in the higher dose group, while a reduction of 6.10 ± 31.86 % at Day 1 and 56.99 ± 9.18 % at Day 5 was observed in the lower dose group. An increase of 29.31 ± 66.84 % at Day 1 was observed in the control group. There is a good correlation between percentage of MVD derived by CD34 staining with percentage of blood volume derived by the two-compartment model (r = 0.806, p = 0.0002). Conclusion: The results showed that the effects of bevacizumab are dose-related. A more gradual drop of blood volume was observed in group treated with bevacizumab 1 mg/kg. On the other hand, a steep and immediate drop of blood volume was observed in group treated with bevacizumab 10 mg/kg. The results suggested potential of DCE-MRI as a sensitive biomarker of MVD and as a reliable non-destructive testing method for time course observation of MVD changes in animals. This facilitates translation and clinical application to early time points after anti-angiogenic therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1317. doi:1538-7445.AM2012-1317