Tissue Deoxyhemoglobin Research Articles

Cerebral Metabolic Stress Is Lower in Patients with Sickle Cell Anemia on Hydroxyurea Therapy

Hydroxyurea (HU) is the only medication available with neuroprotective potential in sickle cell anemia (SCA), yet the physiological mechanisms of this effect remain unclear. We utilized MRI to measure cerebral blood flow (CBF) and oxygen extraction fraction (OEF) to test our hypothesis that HU therapy relieves ongoing cerebral metabolic stress by decreasing OEF in patients with SCA. Brain MRI measured CBF (pseudo-continuous arterial spin labeling), OEF (asymmetric spin echo sequence that measures voxel-wise tissue deoxyhemoglobin) and vasculopathy (magnetic resonance angiography) in prospectively enrolled participants with SCA. FMRIB9s Linear Image Registration Tool individually co-registered CBF and OEF maps to corresponding T1 images, and FMRIB9s Automated Segmentation Tool segmented gray and white matter (GM and WM). For analysis, participants were cohorted by SCA therapy they were receiving at the time of the MRI. Group comparisons between SCA without HU, SCA with HU, and SCA pre-transfusion (pre-tx; MRI up to 24 hours before chronic tx therapy) were made with Kruskal-Wallis or chi-squared test, followed by pairwise comparisons with Mann-Whitney U test. Bivariate correlations were described with Spearman9s rho. Significance was specified as p-value Seventy-nine participants with SCA (70 HbSS, 9 HbSβ 0 thalassemia) underwent MRI. There was no significant difference in age (p = 0.965) or sex (p = 0.471) among treatment cohorts. Hemoglobin (Hb) was significantly different between cohorts (p = 0.001). While the SCA without HU cohort had a significantly lower Hb than both SCA with HU (p = 0.010) and SCA pre-tx (p There was no difference in GM (p = 0.680) or WM (p = 0.736) CBF among the 3 cohorts, even after controlling for age with multiple regression. However, there was a significant difference in GM OEF among cohorts (p To investigate potential mechanisms of metabolic stress reduction, we evaluated the relationship between OEF, total Hb, % Hb A, % Hb F and % Hb S. OEF and Hb were strongly correlated in both GM and WM (GM: spearman9s rho = -0.857, p 2 = 0.737, p = 0.003), and for WM OEF (total Hb: β = -0.041, p 2 = 0.719, p We report the first investigation into the effects of HU on cerebral oxygen metabolism in SCA. Our data suggest that HU mitigates ongoing cerebral metabolic stress by improving cerebral oxygen delivery, allowing reduction in OEF without altering CBF; however, the degree of OEF correction is not as strong as chronic tx therapy. Longitudinal evaluation of these cohorts is needed to determine if the improvement in OEF by HU is sufficient for prevention of stroke and cognitive dysfunction in patients with SCA. Disclosures Fields: Proclara Biosciences: Equity Ownership. Hulbert: Pfizer: Other: Spouse employment at Pfizer.

Land vs. water HIIE effects on muscle oxygenation and physiological parameter responses in postmenopausal women

Muscle oxygenation (MO) status is the dynamic balance between O2 utilization and O2 delivery. Low-impact high-intensity interval exercise MO responses in the exercise and recovery stage are still unclear. We compared the differences in MO and physiological parameters between high-intensity interval water-based exercise (WHIIE) and high-intensity interval land bike ergonomic exercise (LBEHIIE) in postmenopausal women. Eleven postmenopausal women completed WHIIE or LBEHIIE in counter-balanced order. Eight sets were performed and each exercise set included high intensity with 80% heart rate reserve (HRR) in 30 s and dynamic recovery with 50% HRR in 90 s. Muscle tissue oxygen saturation index (TSI), total hemoglobin (tHb), oxy-hemoglobin (O2Hb), and deoxy-hemoglobin (HHb) were recorded. Blood lactate, heart rate and rating of perceived exertion (RPE) were measured at pre and post-exercise. Under similar exercise intensity, RPE in WHIIE was lower than that in LBEHIIE. The heart rate in WHIIE was lower than that in LBEHIIE at 1 and 2 min post-exercise. During the dynamic recovery, TSI, tHb, and O2Hb in water were higher than on land. A negative correlation was found between the change in TSI and lactate concentration (r = − 0.664). WHIIE produced greater muscle oxygenation during dynamic recovery. Muscle TSI% was inversely related to blood lactate concentration during exercise in water.

Renal blood oxygenation level-dependent magnetic resonance imaging to measure renal tissue oxygenation: a statement paper and systematic review.

Tissue hypoxia plays a key role in the development and progression of many kidney diseases. Blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) is the most promising imaging technique to monitor renal tissue oxygenation in humans. BOLD-MRI measures renal tissue deoxyhaemoglobin levels voxel by voxel. Increases in its outcome measure R2* (transverse relaxation rate expressed as per second) correspond to higher deoxyhaemoglobin concentrations and suggest lower oxygenation, whereas decreases in R2* indicate higher oxygenation. BOLD-MRI has been validated against micropuncture techniques in animals. Its reproducibility has been demonstrated in humans, provided that physiological and technical conditions are standardized. BOLD-MRI has shown that patients suffering from chronic kidney disease (CKD) or kidneys with severe renal artery stenosis have lower tissue oxygenation than controls. Additionally, CKD patients with the lowest cortical oxygenation have the worst renal outcome. Finally, BOLD-MRI has been used to assess the influence of drugs on renal tissue oxygenation, and may offer the possibility to identify drugs with nephroprotective or nephrotoxic effects at an early stage. Unfortunately, different methods are used to prepare patients, acquire MRI data and analyse the BOLD images. International efforts such as the European Cooperation in Science and Technology (COST) action ‘Magnetic Resonance Imaging Biomarkers for Chronic Kidney Disease’ (PARENCHIMA) are aiming to harmonize this process, to facilitate the introduction of this technique in clinical practice in the near future. This article represents an extensive overview of the studies performed in this field, summarizes the strengths and weaknesses of the technique, provides recommendations about patient preparation, image acquisition and analysis, and suggests clinical applications and future developments.

Renal Hypoxia: An Important Prognostic Marker in Patients with Chronic Kidney Disease

Background: Blood oxygen level-dependent (BOLD)-MRI is a novel and noninvasive tool that can assess renal oxygenation. The R2* value is a parameter of tissue deoxyhemoglobin concentration detected by BOLD-MRI. The purpose of the current study was to determine the relationships between renal R2* values and clinical parameters and to determine whether renal R2* values were associated with the risk for progression of chronic kidney disease (CKD). Methods: Sixty patients with CKD were enrolled in this prospective observational study in China from March 2013 to August 2014. A region of interest-based BOLD-MRI was performed to obtain cortical and medullary R2* (CR2* and MR2*) values. Data on demographics and clinical characteristics were collected. The primary end point (CKD progression) was defined as an absolute 30% decline in the estimated glomerular filtration rates (eGFR; CKD-Epidemiology Collaboration equations) or initiation of dialysis during follow-up. Results: The CR2* and MR2* values in patients with CKD were significantly higher compared with those of healthy controls. The CR2* levels were positively associated with 24-h urinary protein excretion, blood urea nitrogen, creatinine, and uric acid but negatively associated with baseline eGFR, 24-h creatinine clearance, eGFR slope, serum albumin, and the use of angiotensin II type 1 receptor blockade. The CR2* levels had the highest areas under the curve during follow-up compared with the MR2* levels and medullary cortical ratios. The Kaplan-Meier survival analysis showed that patients with CKD in the lowest tertile of the CR2* levels had the best prognosis compared with the other 2 tertiles. Moreover, baseline eGFR and CR2* tertiles were associated with the progression of CKD in Cox proportional hazard regression models. Only CR2* tertiles correlated negatively with the eGFR slope. Conclusion: We have demonstrated that the clinical feasibility of BOLD-MRI to evaluate renal oxygenation and cortex hypoxia aggravates with the decline of renal function, and cortex hypoxia was a prognostic marker in the progression of CKD.

The Effect of Short and Long Term Endurance Training on Systemic, and Muscle and Prefrontal Cortex Tissue Oxygen Utilisation in 40 - 60 Year Old Women.

PurposeAerobic endurance training (ET) increases systemic and peripheral oxygen utilisation over time, the adaptation pattern not being linear. However, the timing and mechanisms of changes in oxygen utilisation, associated with training beyond one year are not known. This study tested the hypothesis that in women aged 40–60 years performing the same current training load; systemic O2 utilisation (VO2) and tissue deoxyhaemoglobin (HHb) in the Vastus Lateralis (VL) and Gastrocnemius (GAST) would be higher in long term trained (LTT; > 5 yr) compared to a short term trained (STT; 6–24 months) participants during ramp incremental (RI) cycling, but similar during square-wave constant load (SWCL) cycling performed at the same relative intensity (below ventilatory turn point [VTP]); and that pre-frontal cortex (PFC) HHb would be similar between participant groups in both exercise conditions.MethodsThirteen STT and 13 LTT participants performed RI and SWCL conditions on separate days. VO2, and VL, GAST, and PFC HHb were measured simultaneously.ResultsVO2peak was higher in LTT compared to STT, and VO2 was higher in LTT at each relative intensities of 25%, 80% and 90% of VTP in SWCL. HHb in the VL was significantly higher in LTT compared to STT at peak exercise (4.54 ± 3.82 vs 1.55 ± 2.33 μM), and at 25% (0.99 ± 1.43 vs 0.04 ± 0.96 μM), 80% (3.19 ± 2.93 vs 1.14 ± 1.82 μM) and 90% (4.62 ± 3.12 vs 2.07 ± 2.49 μM) of VTP in SWCL.ConclusionsThe additional (12.9 ± 9.3) years of ET in LTT, resulted in higher VO2, and HHb in the VL at peak exercise, and sub—VTP exercise. These results indicate that in women 40–60 years old, systemic and muscle O2 utilisation continues to improve with ET beyond two years.

Elevations in MR Measurements of Whole Brain and Regional Cerebral Blood Flow and Oxygen Extraction Fraction Suggest Cerebral Metabolic Stress in Children with Sickle Cell Disease Unaffected By Overt Stroke

Positron emission tomography (PET) studies have shown that the brain increases cerebral blood flow (CBF) and oxygen extraction fraction (OEF, the fraction of oxygen brain tissue extracts from blood) when oxygen delivery is compromised in adult ischemic stroke. Children with sickle cell disease (SCD) have higher CBF compared to healthy children, suggesting that autoregulatory mechanisms, compensating for compromised oxygen delivery, may underlie the pathophysiology of ischemic stroke in SCD. Until now, evaluation of cerebral oxygen metabolism in children with SCD has been limited to measurement of CBF due to the radiation risks of PET. We used a MR sequence that measures voxel-wise OEF to test our hypothesis that children with sickle cell disease will have elevated whole brain and regional OEF when compared to typically developing, sibling controls without SCD.Thirty-six participants, 8 controls and 28 with SCD (26 HbSS and 2 HbSB0), ages 5-21 years, were recruited from St. Louis Children's Hospital. Participants underwent brain MRI with measurement of CBF via pseudo-continuous arterial spin labeling and OEF via a novel processing of asymmetric spin echo sequence that measures tissue deoxyhemoglobin. CBF and OEF maps were individually co-registered to corresponding T1 images with FMRIB's Linear Image Registration Tool, and gray and white matter were segmented with FMRIB's Automated Segmentation Tool. Visual inspection identified a region of high OEF within the deep white matter of the frontal and parietal lobes in the majority of subjects (figure 1 a,b). OEF maps from control and SCD participants were coregistered and averaged into a single map, and then an OEF threshold of 47.5% was applied to demarcate this "high OEF region" (figure 1c). Hemoglobin (Hb) and hematocrit were obtained in SCD participants, while these values were assumed for the controls. Arterial oxygen content (CaO2) was calculated as 1.36 x Hb x SpO2. Comparisons were made with a Mann-Whitney U test or Student's t-test. Bivariate correlations were tested with Kendall's tau b. Bonferroni correction was used in determining significance. Multivariate linear regression modeling with block entry described covariates associated with CBF.The control and SCD cohorts did not differ in age, gender or SpO2. SCD participants demonstrated higher whole brain, gray matter and white matter CBF and OEF when compared to controls (table 1, figure 1a-b), but there was no difference in whole brain or segmented measures of CBF and OEF between SCD participants with structurally normal brain MRIs (n=16) and silent infarcts (n=12). SCD participants' OEF was higher within the "high OEF region" when compared to controls (table 1), but the regional OEF did not differ between SCD participants with structurally normal brain MRIs versus silent infarcts. Whole brain CBF negatively correlated with age (b = -0.554, p < 0.001), while whole brain OEF did not (b= 0.014, p = 0.921). Lower CaO2 correlated with higher whole brain CBF (b = -0.329, p < 0.016) and higher whole brain OEF (b = -0.587, p < 0.001). CaO2 remained a predictor (β = -0.38, p = 0.009) of CBF when controlling for age (β = -0.63, p < 0.001).We report the first whole brain, segmented and regional analysis of oxygen metabolism, including CBF and OEF, in a pediatric SCD cohort unaffected by overt stroke. Elevation in both CBF and OEF in response to low arterial oxygen content suggests children with SCD are chronically compensating to meet the brain's metabolic demands. OEF is more elevated in children with SCD when compared to healthy controls within the "high OEF region," which coincides with previously reported locations of silent infarcts. We propose that the "high OEF region" provides a tissue signature of vulnerable, metabolically stressed brain that is at risk for future stroke. [Display omitted] [Display omitted] DisclosuresFields:Neurophage: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Neurovascular coupling during cortical spreading depolarization and -depression.

Cortical spreading depolarizations (CSDs) are self-propagating waves of transient loss of neuronal transmembrane ion gradients, followed by prolonged suppression of neuronal activity (spreading depression). CSDs emerge spontaneously in animal models of traumatic brain injury,1 subarachnoid hemorrhage,2 and in focal ischemia3 where they are associated with infarct growth.4 In humans, CSDs have been demonstrated in traumatic brain injury,5 subarachnoid hemorrhage,6,7 and malignant hemispheric stroke,8 and they are believed to be the brain mechanism underlying migraine aura.9 CSDs are associated with dramatic changes in cerebral blood flow (CBF). During the depolarization phase of CSDs induced in healthy and well-perfused brain tissue in animal models, an early hyperemic response is observed, typically followed by prolonged oligemia after the neuronal repolarization. Despite the initial CBF increase, tissue hypoxia may develop in more distant territories of capillary supply.10,11 Similar CBF changes have been observed in patients with migraine aura.12–14 In the injured brain, CSDs can be accompanied by severe initial CBF reduction instead of a CBF increase during the depolarization phase, termed spreading ischemia.15 When this inverse hemodynamic response is observed, the energy-dependent recovery from CSD is delayed in a characteristic fashion, indicating a severe mismatch between oxygen supply and demand2 and a high risk of tissue damage.16 In rat and cat models of focal ischemia, CSD-related CBF transients range from monophasic, positive CBF responses in peri-ischemic tissue, over biphasic transients in mildly ischemic tissue, to negative CBF transients in more severe ischemia.17–19 During CSD in animal models, capillary flow patterns become severely disturbed.10,20,21 The passage of a CSD causes erythrocytes in some capillaries to reduce their speed, whereas other capillaries reveal 4-fold increases in flow or higher. …

Muscle oxygen changes following Sprint Interval Cycling training in elite field hockey players.

This study examined the effects of Sprint Interval Cycling (SIT) on muscle oxygenation kinetics and performance during the 30-15 intermittent fitness test (IFT). Twenty-five women hockey players of Olympic standard were randomly selected into an experimental group (EXP) and a control group (CON). The EXP group performed six additional SIT sessions over six weeks in addition to their normal training program. To explore the potential training-induced change, EXP subjects additionally completed 5 x 30s maximal intensity cycle testing before and after training. During these tests near-infrared spectroscopy (NIRS) measured parameters; oxyhaemoglobin + oxymyoglobin (HbO2+ MbO2), tissue deoxyhaemoglobin + deoxymyoglobin (HHb+HMb), total tissue haemoglobin (tHb) and tissue oxygenation (TSI %) were taken. In the EXP group (5.34±0.14 to 5.50±0.14m.s-1) but not the CON group (pre = 5.37±0.27 to 5.39±0.30m.s-1) significant changes were seen in the 30-15IFT performance. EXP group also displayed significant post-training increases during the sprint cycling: ΔTSI (−7.59±0.91 to −12.16±2.70%); ΔHHb+HMb (35.68±6.67 to 69.44±26.48μM.cm); and ΔHbO2+ MbO2 (−74.29±13.82 to −109.36±22.61μM.cm). No significant differences were seen in ΔtHb (−45.81±15.23 to −42.93±16.24). NIRS is able to detect positive peripheral muscle oxygenation changes when used during a SIT protocol which has been shown to be an effective training modality within elite athletes.

Abstract 285: Renal Inflammation and Injury Markers Correlate Directly With Cortical and Fractional Hypoxia Measured With Blood Oxygen Level Dependent (BOLD) MR in Human Atherosclerotic Renal Artery Stenosis

Background: Atherosclerotic renal artery stenosis (ARAS) reduces renal blood flow (RBF) and amplifies regional kidney hypoxia, but their relationship to tissue inflammation and injury markers is poorly understood. We tested the hypothesis that renal injury, reflected by renal vein levels of neutrophil gelatinase associated lipocalin (NGAL) and inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1) would be magnified with severe occlusive vascular disease in humans with ARAS. Methods: Inpatient studies performed in patients with ARAS (n=40, 71.3±11% occlusion by CT angiography) or essential hypertension (EH) (n=30), during fixed Na+ intake and ACE/ARB Rx. Single-kidney cortical and medullary perfusion and RBF were measured using multidetector CT, and glomerular filtration rate (GFR) by iothalamate clearance. Tissue deoxyhemoglobin levels (R2*) and fractional kidney hypoxia (% of axial area with R2*&gt;30/s) were measured by BOLD-MRI at 3T. Results: Single kidney RBF, cortical and medullary perfusion were reduced in the post-stenotic kidney, as was GFR. Renal vein NGAL, MCP-1 and fractional hypoxia were higher in patients with ARAS than EH. NGAL and MCP-1 levels correlated directly with cortical R2* and fractional hypoxia (r = 0.52, P &lt;0 .0001 and r = 0.4, P = 0.0006) and with the degree of artey stenosis (r = 0.37, P = 0.04 and r = 0.35, P = 0.05). GFR correlated inversely with NGAL (r= - 0.5, P &lt;0.0001). Conclusions: Our results demonstrate that elevated renal venous markers of kidney inflammation (MCP-1) and injury (NGAL) in ARAS are correlated with the severity of tissue hypoxia as measured by BOLD MR, suggesting a possible link between kidney inflammation and hypoxia.

A Novel Pilot Study Using Spatial Frequency Domain Imaging to Assess Oxygenation of Perforator Flaps During Reconstructive Breast Surgery

Although various methods exist for monitoring flaps during reconstructive surgery, surgeons primarily rely on assessment of clinical judgment. Early detection of vascular complications improves rate of flap salvage. Spatial frequency domain imaging (SFDI) is a promising new technology that provides oxygenation images over a large field of view. The goal of this clinical pilot study is to use SFDI in perforator flap breast reconstruction. Three women undergoing unilateral breast reconstruction after mastectomy were enrolled for our study. The SFDI system was deployed in the operating room, and images acquired over the course of the operation. Time points included images of each hemiabdominal skin flap before elevation, the selected flap after perforator dissection, and after microsurgical transfer. Spatial frequency domain imaging was able to measure tissue oxyhemoglobin concentration (ctO2Hb), tissue deoxyhemoglobin concentration, and tissue oxygen saturation (stO2). Images were created for each metric to monitor flap status and the results quantified throughout the various time points of the procedure. For 2 of 3 patients, the chosen flap had a higher ctO2Hb and stO2. For 1 patient, the chosen flap had lower ctO2Hb and stO2. There were no perfusion deficits observed based on SFDI and clinical follow-up. The results of our initial human pilot study suggest that SFDI has the potential to provide intraoperative oxygenation images in real-time during surgery. With the use of this technology, surgeons can obtain tissue oxygenation and hemoglobin concentration maps to assist in intraoperative planning; this can potentially prevent complications and improve clinical outcome.

Stent Revascularization Restores Cortical Blood Flow and Reverses Tissue Hypoxia in Atherosclerotic Renal Artery Stenosis but Fails to Reverse Inflammatory Pathways or Glomerular Filtration Rate

Atherosclerotic renal artery stenosis (ARAS) is known to reduce renal blood flow, glomerular filtration rate (GFR) and amplify kidney hypoxia, but the relationships between these factors and tubulointerstitial injury in the poststenotic kidney are poorly understood. The purpose of this study was to examine the effect of renal revascularization in ARAS on renal tissue hypoxia and renal injury. Inpatient studies were performed in patients with ARAS (n=17; >60% occlusion) before and 3 months after stent revascularization, or in patients with essential hypertension (n=32), during fixed Na(+) intake and angiotensin converting enzyme/angiotensin receptors blockers Rx. Single kidney cortical, medullary perfusion, and renal blood flow were measured using multidetector computed tomography, and GFR by iothalamate clearance. Tissue deoxyhemoglobin levels (R(2)*) were measured by blood oxygen level-dependent MRI at 3T, as was fractional kidney hypoxia (percentage of axial area with R(2)*>30/s). In addition, we measured renal vein levels of neutrophil gelatinase-associated lipocalin, monocyte chemoattractant protein-1, and tumor necrosis factor-α. Pre-stent single kidney renal blood flow, perfusion, and GFR were reduced in the poststenotic kidney. Renal vein neutrophil gelatinase-associated lipocalin, tumor necrosis factor-α, monocyte chemoattractant protein-1, and fractional hypoxia were higher in untreated ARAS than in essential hypertension. After stent revascularization, fractional hypoxia fell (P<0.002) with increased cortical perfusion and blood flow, whereas GFR and neutrophil gelatinase-associated lipocalin, monocyte chemoattractant protein-1, and tumor necrosis factor-α remained unchanged. These data demonstrate that despite reversal of renal hypoxia and partial restoration of renal blood flow after revascularization, inflammatory cytokines and injury biomarkers remained elevated and GFR failed to recover in ARAS. Restoration of vessel patency alone failed to reverse tubulointerstitial damage and partly explains the limited clinical benefit of renal stenting. These results identify potential therapeutic targets for recovery of kidney function in renovascular disease.

Abstract P3-06-27: Dynamic tomographic optical breast imaging (TOBI) to monitor response to neoadjuvant therapy in breast cancer

Abstract Background: Near-infrared optical measurements have been recently shown to offer a promising non-invasive way for monitoring breast neoadjuvant chemotherapy (NAC) and predicting outcome. In particular, snapshots of tissue oxy and deoxy-hemoglobin concentration as well as water and lipid content have been demonstrated to be sensitive to therapy-induced changes. In this study, we extend optical measurements to capture additional hemodynamic and metabolic biomarkers revealed by dynamically imaging breast tissue during fractional mammographic compression. Using our dynamic tomographic optical breast imaging (TOBI) system we evaluate the early prediction performance of this advanced technology. Methods: We are conducting a pilot feasibility study in female patients with unilateral locally advanced breast cancer undergoing standard-of-care NAC. Pre-treatment and day 7 post-treatment TOBI scans are obtained, with additional (optional) scans on day 1 of each subsequent chemotherapy cycle. Both breasts are compressed in turn to 4–8 lbs of force, and optical images are acquired once every 2 seconds over two minutes. Time-resolved oxy-(HbO), deoxy-(HbR), and total-(HbT) hemoglobin concentration and hemoglobin oxygen saturation (SO2) are calculated. The compression-induced rate of change of HbT correlates with changes in tissue blood volume indicative of biomechanical properties. The evolution of tissue SO2 is modeled to obtain an index of the ratio of oxygen metabolism to blood flow. Therapy induced changes are quantified, and comparisons between changes in responders vs. non-responders are performed (response is defined here as &amp;gt;50% reduction in the largest tumor diameter). Results: We have enrolled 20 patients so far, of which 90% (N = 18) completed both the day 0 and day 7 scans. 17 patients have undergone surgery at this point. We focused our initial analysis on 5 HER2+ patients, of which two were non-responders, and three were responders according to our criteria. Four patients received taxol+herceptin+lapatinib, while the other received taxol+lapatinib only. In this small subgroup, the non-responders had an average increase of 1% in total hemoglobin concentration (HbT) from day 0 to day 7, while the responders had an average 12% decrease in HbT, respectively. We also noted different trends in the evolution of the tissue oxygen consumption to blood flow ratio, which increased 32% in non-responders from day 0 to day 7, while decreasing 11% in responders. Conclusions: The large percentage of enrolled patients that completed both initial scans demonstrates the feasibility of using dynamic optical breast tomography for breast neoadjuvant chemotherapy monitoring. Results in a small cohort of 5 HER2+ patients suggested a decreasing trend in HbT for responders as observed by previous studies. We also report for the first time an increase in the metabolic ratio of oxygen consumption to blood flow in non-responders vs. a decrease in responders. These initial results of our on-going study suggest that dynamic TOBI can detect changes due to treatment and may have predictive value for the treatment outcome and supports further studies of this non-invasive and portable tool for chemotherapy monitoring. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-27.

A generalized procedure for calibrated MRI incorporating hyperoxia and hypercapnia

Calibrated MRI techniques use the changes in cerebral blood flow (CBF) and blood oxygenation level-dependent (BOLD) signal evoked by a respiratory manipulation to extrapolate the total BOLD signal attributable to deoxyhemoglobin at rest (M). This parameter can then be used to estimate changes in the cerebral metabolic rate of oxygen consumption (CMRO(2)) based on task-induced BOLD and CBF signals. Different approaches have been described previously, including addition of inspired CO(2) (hypercapnia) or supplemental O(2) (hyperoxia). We present here a generalized BOLD signal model that reduces under appropriate conditions to previous models derived for hypercapnia or hyperoxia alone, and is suitable for use during hybrid breathing manipulations including simultaneous hypercapnia and hyperoxia. This new approach yields robust and accurate M maps, in turn allowing more reliable estimation of CMRO(2) changes evoked during a visual task. The generalized model is valid for arbitrary flow changes during hyperoxia, thus benefiting from the larger total oxygenation changes produced by increased blood O(2) content from hyperoxia combined with increases in flow from hypercapnia. This in turn reduces the degree of extrapolation required to estimate M. The new procedure yielded M estimates that were generally higher (7.6 ± 2.6) than those obtained through hypercapnia (5.6 ± 1.8) or hyperoxia alone (4.5 ± 1.5) in visual areas. These M values and their spatial distribution represent a more accurate and robust depiction of the underlying distribution of tissue deoxyhemoglobin at rest, resulting in more accurate estimates of evoked CMRO(2) changes.

Diffuse optical spectroscopic imaging correlates with final pathological response in breast cancer neoadjuvant chemotherapy

Diffuse optical spectroscopic imaging (DOSI) non-invasively and quantitatively measures tissue haemoglobin, water and lipid. Pilot studies in small groups of patients demonstrate that DOSI may be useful for longitudinal monitoring and predicting breast cancer neoadjuvant chemotherapy pathological response. This study evaluates the performance of a bedside DOSI platform in 34 breast cancer patients followed for several months. DOSI optical endpoints obtained at multiple timepoints are compared with final pathological response. Thirty-six stage II/III breast cancers (34 patients) were measured in vivo with DOSI prior to, in the middle of and after the completion of pre-surgical neoadjuvant chemotherapy. Cancer therapies ranged from standard anthracyclines to targeted therapies. Changes in DOSI-measured parameters at each timepoint were compared against final surgical pathology. Absolute changes in the tumour-to-normal (T/N) ratio of tissue deoxyhaemoglobin concentration (ctHHb) and relative changes in the T/N ratio of a tissue optical index (TOI) were most sensitive and correlate to pathological response. Changes in ctHHb and TOI were significantly different between tumours that achieved pathological complete response (pCR) versus non-pCR. By therapy midpoint, mean TOI-T/N changes were 47±8 versus 20±5 per cent for pCR versus non-pCR subjects, respectively (Z=0.011). Changes in ctHHb and TOI scaled significantly with the degree of pathological response (non-, partial and complete). DOSI measurements of TOI separated pCR from non-pCR by therapy midpoint regardless of drug or dosing strategy. This approach is well suited to monitoring breast tumour response and may provide feedback for optimizing therapeutic outcomes and minimizing side-effects.

Effects of sepsis on venous microcirculation: non-invasive evaluation by quantitative near-infrared spectroscopy

Sepsis has several effects on microcirculation, including microthrombosis, interstitial edema and reduced reactivity of arteriolar tone leading to shunt areas [1]. Little is known about the effects of sepsis on the venous component of microcirculation. Changes of venular compliance and volume of the venular bed may affect cardiac preload, which has a key role in occurrence of cardiac failure. Near-infrared spectroscopy (NIRS) is a widely used, non-invasive technique that enables one to quantify the tissue oxyhemoglobin and deoxyhemoglobin (Hb) concentration, through which microvascular blood flow, compliance and oxygen consumption can be extrapolated [2]. The aim of our study was to evaluate the effects of sepsis on venous compliance and volume of the venular bed.

Evaluation of Renal Hypoxia in Diabetic Mice by BOLD MRI

Renal hypoxia has been proposed to be a pathophysiologic feature of diabetic kidney disease but it has been difficult to demonstrate in vivo, particularly in mouse models of diabetes. The objective of this work was to examine the sensitivity of blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) to assess renal oxygenation in vivo in a mouse model of diabetic kidney disease, the db/db mice. Kidney BOLD MRI studies were performed on a 3.0 T scanner using multiple gradient echo sequence with a custom-designed surface coil to acquire T2*-weighted images. Studies were performed in 10-week-old db/db mice (n = 7) and db/m controls (n = 6). R2* is a measure of the tissue deoxyhemoglobin concentration and higher values of R2* are associated with hypoxia. The db/db mice had higher medullary (43.1 ± 5.1 s⁻¹ vs. 32.3 ± 3.7⁻¹ s, P = 0.001) and cortical R2* (31.7 ± 3.1 s⁻¹ vs. 27.1 ± 4.1 s⁻¹, P = 0.04) values. Using pimonidazole staining as a marker of kidney hypoxia, in kidney sections from 10-week-old db/db mice neither cortex nor medulla had significant differences as compared with 10-week-old db/m mice (cortex: db/db 2.14 ± 0.05 vs. db/m 2.02 ± 0.28, medulla: db/db 2.81 ± 0.08 vs. db/m 2.6 ± 0.08). The db/db mice demonstrated further increased cortical and medullary hypoxia when scanned again at 15 weeks of age. The report shows that renal BOLD MRI is a sensitive method for the in vivo evaluation of renal hypoxia in a mouse model of diabetic kidney disease where progressive renal hypoxia can be documented over time. BOLD MRI may be useful to monitor therapeutic interventions that may improve tissue hypoxia in the diabetic kidney.

Diffuse optical spectroscopy measurements of healing in breast tissue after core biopsy: case study

Diffuse optical spectroscopy (DOS) has been used to monitor and predict the effects of neoadjuvant (i.e., presurgical) chemotherapy in breast cancer patients in several pilot studies. Because patients with suspected breast cancers undergo biopsy prior to treatment, it is important to understand how biopsy trauma influences DOS measurements in the breast. The goal of this study was to measure the effects of a standard core breast biopsy on DOS measurements of tissue deoxyhemoglobin, hemoglobin, water, and bulk lipid concentrations. We serially monitored postbiopsy effects in the breast tissue in a single subject (31-year-old premenopausal female) with a 37x18x20 mm fibroadenoma. A baseline measurement and eight weekly postbiopsy measurements were taken with a handheld DOS imaging instrument. Our instrument used frequency domain photon migration combined with broadband steady-state spectroscopy to characterize tissues via quantitative measurements of tissue absorption and reduced scattering coefficients from 650 to 1000 nm. The concentrations of significant near-infrared (NIR) absorbers were mapped within a 50 cm(2) area over the biopsied region. A 2-D image of a contrast function called the tissue optical index (TOI=deoxyhemoglobinxwaterbulk lipid) was generated and revealed that a minimum of 14 days postbiopsy was required to return TOI levels in the biopsied area to their prebiopsy levels. Changes in the TOI images of the fibroadenoma also reflected the progression of the patient's menstrual cycle. DOS could therefore be useful in evaluating both wound-healing response and the effects of hormone and hormonal therapies in vivo.

The significance of BOLD MRI in differentiation between renal transplant rejection and acute tubular necrosis

Blood oxygen level-dependent MRI (BOLD MRI) can be used to assess intra-renal oxygen bioavailability by measuring the R2(*) level, which reflects tissue deoxyhaemoglobin levels. This study was designed to identify the significance of BOLD MRI in differentiation of acute rejection (AR) and acute tubular necrosis (ATN) in patients within 6 months after kidney transplantation. Eighty-two patients with normal graft function and 28 patients with biopsy-proven AR (n = 21) or ATN (n = 7) were enrolled. Patients with normal functioning allograft underwent BOLD MRI within 2 to 3 weeks post-transplantation, while patients with AR and ATN underwent BOLD MRI within 6 days before or after kidney transplant biopsy. Cortical R2(*) (CR2(*)) and medullary R2(*) (MR2(*)) levels were measured. The mean CR2(*) level was significantly higher in the ATN group (15.25 +/- 1.03/s) compared to the normal group (13.35 +/- 2.31/s, P = 0.028) and AR group (12.02 +/- 1.72/s, P = 0.001). There was a significant difference also between the AR group and normal group on CR2(*) levels (P = 0.013). The mean MR2(*) level was significantly lower in the AR group (14.02 +/- 2.68/s) compared to the normal group (16.66 +/- 2.82/s, P < 0.001) and ATN group (19.47 +/- 1.62/s, P < 0.001). There was also a significant difference between the ATN group and normal group on MR2(*) levels (P = 0.011). There were no correlations between characteristics such as patient age, post-operation time, post-biopsy time, Scr level, HB level, urine output volume, MAP level, CNI trough concentration and R2(*) levels, except between MAP level and CR2(*) level (P = 0.029). BOLD MRI could be a valuable method to discriminate between AR and ATN by measuring tissue oxygen bioavailability in early kidney allograft dysfunction.

The Use of Magnetic Resonance to Evaluate Tissue Oxygenation in Renal Artery Stenosis

Vascular occlusive disease poses a threat to kidney viability, but whether the events leading to injury and eventual fibrosis actually entail reduced oxygenation and regional tissue ischemia is unknown. Answering this question has been difficult because of the lack of an adequate method to assess tissue oxygenation in humans. BOLD (blood oxygen-level-dependent) magnetic resonance imaging detects changes in tissue deoxyhemoglobin during maneuvers that affect oxygen consumption, therefore this technique was used to image and analyze cortical and medullary segments of 50 kidneys in 25 subjects undergoing magnetic resonance (MR) angiography to diagnose renal artery stenosis (RAS). Magnetic rate of relaxation (R2*) positively correlates with deoxyhemoglobin levels and was therefore used as a surrogate measure of tissue oxygenation. Furosemide was administered to examine the effect of inhibiting energy-dependent electrolyte transport on tissue oxygenation in subjects with renovascular disease. In 21 kidneys with normal nephrograms, administration of furosemide led to a 20% decrease in medullary R2* (P < 0.01) and an 11.2% decrease in cortical R2*. In normal-size kidneys downstream of high-grade renal arterial stenoses, R2* was elevated at baseline, but fell after furosemide. In contrast, atrophic kidneys beyond totally occluded renal arteries demonstrated low levels of R2* that did not change after furosemide. In kidneys with multiple arteries, localized renal artery stenoses produced focal elevations of R2*, suggesting areas of deoxyhemoglobin accumulation. These results suggest that BOLD MR coupled with a method to suppress tubular oxygen consumption can be used to evaluate regional tissue oxygenation in the human kidney affected by vascular occlusive disease.

BOLD-MRI assessment of intrarenal oxygenation and oxidative stress in patients with chronic kidney allograft dysfunction

Blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) uses deoxyhemoglobin as an endogenous contrast agent for the noninvasive assessment of tissue oxygen bioavailability. We hypothesized that intrarenal oxygenation was impaired in patients with chronic allograft nephropathy (CAN). Ten kidney-transplant recipients with CAN and nine healthy volunteers underwent BOLD-MRI. Medullary R2* (MR2*) and cortical R2* (CR2*) levels (measures directly proportional to tissue deoxyhemoglobin levels) were determined alongside urine and serum markers of oxidative stress (OS): hydrogen peroxide (H(2)O(2)), F(2)-isoprostanes, total nitric oxide (NO), heat shock protein 27 (HSP27), and total antioxidant property (TAOP). Mean MR2* and CR2* levels were significantly decreased in CAN (increased local oxyhemoglobin concentration) compared with healthy volunteers (20.7 +/- 1.6 vs. 23.1 +/- 1.8/s, P = 0.03 and 15.9 +/- 1.9 vs. 13.6 +/- 2.3/s, P = 0.05, respectively). There was a significant increase in serum and urine levels of H(2)O(2) and serum HSP27 levels in patients with CAN. Conversely, urine NO levels and TAOP were significantly increased in healthy volunteers. Multiple linear regression analyses showed a significant association between MR2* and CR2* levels and serum/urine biomarkers of OS. BOLD-MRI demonstrated significant changes in medullary and cortical oxygen bioavailability in allografts with CAN. These correlated with serum/urine biomarkers of OS, suggesting an association between intrarenal oxygenation and OS.