Noninvasive monitoring of murine tumor blood flow during and after photodynamic therapy provides early assessment of therapeutic efficacy

Department of Physics and Astronomy, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Clinical Cancer Research (Impact Factor: 8.19). 05/2005; 11(9):3543-52. DOI: 10.1158/1078-0432.CCR-04-2582
Source: PubMed

ABSTRACT To monitor tumor blood flow noninvasively during photodynamic therapy (PDT) and to correlate flow responses with therapeutic efficacy.
Diffuse correlation spectroscopy (DCS) was used to measure blood flow continuously in radiation-induced fibrosarcoma murine tumors during Photofrin (5 mg/kg)/PDT (75 mW/cm2, 135 J/cm2). Relative blood flow (rBF; i.e., normalized to preillumination values) was compared with tumor perfusion as determined by power Doppler ultrasound and was correlated with treatment durability, defined as the time of tumor growth to a volume of 400 mm3. Broadband diffuse reflectance spectroscopy concurrently quantified tumor hemoglobin oxygen saturation (SO2).
DCS and power Doppler ultrasound measured similar flow decreases in animals treated with identical protocols. DCS measurement of rBF during PDT revealed a series of PDT-induced peaks and declines dominated by an initial steep increase (average +/- SE: 168.1 +/- 39.5%) and subsequent decrease (59.2 +/- 29.1%). The duration (interval time; range, 2.2-15.6 minutes) and slope (flow reduction rate; range, 4.4 -45.8% minute(-1)) of the decrease correlated significantly (P = 0.0001 and 0.0002, r2= 0.79 and 0.67, respectively) with treatment durability. A positive, significant (P = 0.016, r2= 0.50) association between interval time and time-to-400 mm3 was also detected in animals with depressed pre-PDT blood flow due to hydralazine administration. At 3 hours after PDT, rBF and SO2 were predictive (P < or = 0.015) of treatment durability.
These data suggest a role for DCS in real-time monitoring of PDT vascular response as an indicator of treatment efficacy.

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    • "Intuitively, the random flow model might be considered the best model with which to fit DCS data. In practice, however, it has been observed that the diffusion model fits the autocorrelation curves rather well over a broad range of tissue types [6], [7], [10], [13], [15], [16], [19]–[21], [27]–[33]. For the case of diffusive motion, <Δr 2 (τ )> = 6D B τ , where D B is the effective Brownian diffusion coefficient of scatterers. "
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    ABSTRACT: Near-infrared diffuse correlation spectroscopy (DCS) has recently been employed for noninvasive acquisition of blood flow information in deep tissues. Based on the established correlation diffusion equation, the light intensity autocorrelation function detected by DCS is determined by a blood flow index áDB, tissue absorption coefficient ìa, reduced scattering coefficient ìs, and a coherence factor â. The present study is designed to investigate the possibility of extracting multiple parameters such as ìa, ìs, â, and áDB through fitting one single autocorrelation function curve and evaluate the performance of different fitting methods. For this purpose, computer simulations, tissue-like phantom experiments and in-vivo tissue measurements were utilized. The results suggest that it is impractical to simultaneously fit áDB and ìa or áDB and ìs from one single autocorrelation function curve due to the large crosstalk between these paired parameters. However, simultaneously fitting â and áDB is feasible and generates more accurate estimation with smaller standard deviation compared to the conventional two-step fitting method (i.e., first calculating â and then fitting áDB). The outcomes from this study provide a crucial guidance for DCS data analysis.
    IEEE transactions on bio-medical engineering 11/2012; 60(2). DOI:10.1109/TBME.2012.2226885 · 2.23 Impact Factor
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    • "DCS is a relatively new technique which can directly probe blood flow in deep tissues including the cerebral cortex (Cheung et al., 2001; Culver et al., 2005; Dietsche et al., 2007; Durduran et al., 2009, 2010; Edlow et al., 2010; Gagnon et al., 2008; Li et al., 2008; Shang et al., 2011a,b; Zirak et al., 2010). Blood flow variations measured by DCS have been validated in various organs and tissues against other standards, including Doppler ultrasound (Roche-Labarbe et al., 2010), power Doppler ultrasound (Yu et al., 2005), laser Doppler (Durduran, 2004; Shang et al., 2011a), Xenon-CT (Kim et al., 2010), fluorescent microsphere measurement (Zhou et al., 2009), and perfusion MRI (Yu et al., 2007). The hybrid NIR optical instrument offers direct and simultaneous measurements of CBF and cerebral oxygenation in microvasculature within the same region of cerebral cortex, which may bring new and informative insights about LFOs in local brain tissues. "
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    ABSTRACT: Spontaneous low frequency oscillations (LFOs) around 0.1 Hz have been observed in mean arterial pressure (MAP) and cerebral blood flow velocity (CBFV). Previous studies have shown that cerebral autoregulation in major arteries can be assessed by quantification of the phase shift between LFOs of MAP and CBFV. However, many cerebral diseases are associated with abnormal microvasculature and tissue dysfunction in brain, and quantification of these abnormalities requires direct measurement of cerebral tissue hemodynamics. This pilot study used a novel hybrid near-infrared diffuse optical instrument to noninvasively and simultaneously detect LFOs of cerebral blood flow (CBF) and cerebral oxygenation (i.e., oxygenated/deoxygenated/total hemoglobin concentration: [HbO(2)]/[Hb]/THC) in human prefrontal cortex. Using the hybrid instrument and a finger plethysmograph, the dynamic changes of CBF, [HbO(2)], [Hb], THC and MAP were concurrently measured in 15 healthy subjects at rest, during 70° head-up-tilting (HUT) and during enforced breathing at 0.1 Hz. The LFOs were extracted from the measured variables using power spectral analysis, and the phase shifts and coherences of LFOs between MAP and each of the measured hemodynamic variables were calculated from the corresponding transfer functions. Levels of coherence (>0.4) were used to judge the success of LFO measurements. We found that CBF, [HbO(2)] and THC were reliable hemodynamic parameters in detecting LFOs and HUT was the most robust and stable protocol for quantifying phase shifts of hemodynamic LFOs. Comparing with other relevant studies, similar success rates for detecting cerebral LFOs have been achieved in our study. The phase shifts of LFOs in CBF were also close to those in CBFV reported by other groups, although the results in cerebral oxygenation measurements during enforced breathing varied across studies. Future study will investigate cerebral LFOs in patients with cerebral impairment and evaluate their cerebral autoregulation capabilities and neurocognitive functions via the quantification of LFO phase shifts.
    NeuroImage 05/2012; 62(3):1445-54. DOI:10.1016/j.neuroimage.2012.05.069 · 6.36 Impact Factor
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    • "However, while increased oxy-or total hemoglobin concentrations as measured by NIRS may suggest an increase in blood flow, this assessment is also only an indirect estimate of tissue blood flow. Near-infrared diffuse correlation spectroscopy (DCS) is an emerging technique for continuous, non-invasive, and direct measurement of relative change in blood flow (rBF) in deep tissues (Cheung et al., 2001; Culver et al., 2003; Dietsche et al., 2007; Durduran et al., 2004,2009; Gagnon et al., 2008; Li et al., 2008; Sunar et al., 2006; Yu et al., 2005b,2006; Zhou et al., 2007,2009) including skeletal muscle (Shang et al., 2009,2010; Yu et al., 2005a,2007). DCS has been validated to measure rBF by other standards including Doppler ultrasound (Buckley et al., 2009), laser Doppler (Durduran, 2004), Xenon-CT (Kim et al., 2010), and arterial-spin-labeled MRI (Durduran et al., 2004; Yu et al., 2007). "
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    ABSTRACT: Increase in tissue blood flow is one of the most acknowledged potential effects of massage; however, actual research studies examining this phenomenon are inconsistent and inconclusive. One possible reason for continued uncertainty regarding this topic is methodology, specifically how tissue blood flow is measured because limitations exist in previously utilized technologies. Near-infrared spectroscopy (NIRS) affords massage researchers a versatile and non-invasive measurement option by providing dynamic information on oxy- and deoxy-hemoglobin concentrations, total hemoglobin concentration, and blood oxygen saturation in deep tissue. Near-infrared diffuse correlation spectroscopy (DCS) is an innovative technique for continuous non-invasive measurement of blood flow in deep tissue. The combination of these two technologies has resulted in a novel hybrid diffuse optical instrument for simultaneous measurement of limb muscle blood flow and oxygenation. The purposes of this short report are to review previous blood flow measurement techniques and limitations in massage therapy research, introduce a novel hybrid near-infrared diffuse optical instrument that addresses previous limitations in the assessment of hemodynamic properties, outline a proposed massage therapy pilot study utilizing the novel measurement technology, and present sample data from a pilot participant using the introduced novel technology.
    Journal of bodywork and movement therapies 01/2012; 16(1):22-8. DOI:10.1016/j.jbmt.2011.01.018
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