Chandra M. Sehgal

Use of gray value distribution of run lengths for texture analysis

Abstract Most of the texture measures based on run lengths use only the lengths of the runs and their distribution. We propose to use the gray value distribution of the runs to define two new features, viz., low gray level run emphasis ( LGRE ) and high gray level run emphasis ( HGRE ).

Noninvasive Monitoring of MurineTumor Blood Flow During and After PhotodynamicTherapy Provides Early Assessment of Therapeutic Efficacy

Purpose: To monitor tumor blood flow noninvasively during photodynamic therapy (PDT) and to correlate flow responses with therapeutic efficacy. Experimental Design: 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). Results: 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 ≤ 0.015) of treatment durability. Conclusion: These data suggest a role for DCS in real-time monitoring of PDT vascular response as an indicator of treatment efficacy.

Epidermal growth factor receptor inhibition modulates the microenvironment by vascular normalization to improve chemotherapy and radiotherapy efficacy.

Background Epidermal growth factor receptor (EGFR) inhibitors have shown only modest clinical activity when used as single agents to treat cancers. They decrease tumor cell expression of hypoxia-inducible factor 1-α (HIF-1α) and vascular endothelial growth factor (VEGF). Hypothesizing that this might normalize tumor vasculature, we examined the effects of the EGFR inhibitor erlotinib on tumor vascular function, tumor microenvironment (TME) and chemotherapy and radiotherapy sensitivity. Methodology/Principal Findings Erlotinib treatment of human tumor cells in vitro and mice bearing xenografts in vivo led to decreased HIF-1α and VEGF expression. Treatment altered xenograft vessel morphology assessed by confocal microscopy (following tomato lectin injection) and decreased vessel permeability (measured by Evans blue extravasation), suggesting vascular normalization. Erlotinib increased tumor blood flow measured by Power Doppler ultrasound and decreased hypoxia measured by EF5 immunohistochemistry and tumor O2 saturation measured by optical spectroscopy. Predicting that these changes would improve drug delivery and increase response to chemotherapy and radiation, we performed tumor regrowth studies in nude mice with xenografts treated with erlotinib and either radiotherapy or the chemotherapeutic agent cisplatin. Erlotinib therapy followed by cisplatin led to synergistic inhibition of tumor growth compared with either treatment by itself (p<0.001). Treatment with erlotinib before cisplatin led to greater tumor growth inhibition than did treatment with cisplatin before erlotinib (p = 0.006). Erlotinib followed by radiation inhibited tumor regrowth to a greater degree than did radiation alone, although the interaction between erlotinib and radiation was not synergistic. Conclusions/Significance EGFR inhibitors have shown clinical benefit when used in combination with conventional cytotoxic therapy. Our studies show that targeting tumor cells with EGFR inhibitors may modulate the TME via vascular normalization to increase response to chemotherapy and radiotherapy. These studies suggest ways to assess the response of tumors to EGFR inhibition using non-invasive imaging of the TME.

Cerebral hemodynamics in preterm infants during positional intervention measured with diffuse correlation spectroscopy and transcranial Doppler ultrasound

Four very low birth weight, very premature infants were monitored during a 12 degrees postural elevation using diffuse correlation spectroscopy (DCS) to measure microvascular cerebral blood flow (CBF) and transcranial Doppler ultrasound (TCD) to measure macrovascular blood flow velocity in the middle cerebral artery. DCS data correlated significantly with peak systolic, end diastolic, and mean velocities measured by TCD (p(A) =0.036, 0.036, 0.047). Moreover, population averaged TCD and DCS data yielded no significant hemodynamic response to this postural change (p>0.05). We thus demonstrate feasibility of DCS in this population, we show correlation between absolute measures of blood flow from DCS and blood flow velocity from TCD, and we do not detect significant changes in CBF associated with a small postural change (12 degrees ) in these patients.

Measurement and use of acoustic nonlinearity and sound speed to estimate composition of excised livers

The acoustic nonlinearity parameter B/A and sound speed c have been determined for excised normal and abnormal human livers at 20-37 degrees C. These values are compared with analytic measurements of fat and water content of tissues. The results show that normal liver containing 71.0% water and 2.9% fat by weight has a B/A value of 6.75 and sound speed of 1592 m/s at 37 degrees C. Both these parameters increase at an average rate of 0.026 degrees C and 1.5 m/s/degrees C, respectively, as the temperature is raised from 20 to 37 degrees C. Fatty liver (24% fat by weight) exhibits highest B/A (9.12) and lowest c (1522 m/s) of all the livers studied. In contrast to normal livers sound speed in such a liver was found to decrease with temperature. Based on the acoustic and composition measurements, quantitative correlations of B/A and c with fat-water composition have been developed. Inversion of these relationships provide a simple method to determine composition of a tissue sample from B/A and c measurements.

A Review of Breast Ultrasound

Frequent advances in transducer design, electronics, computers, and signal processing have improved the quality of ultrasound images to the extent that sonography is now a major mode of imaging for the clinical diagnosis of breast cancer. Breast ultrasound is routinely used for differentiating cysts and solid nodules with high specificity. In combination with mammography, ultrasound is used to characterize solid masses as benign or malignant. There is growing interest in using Doppler ultrasound and contrast agents for measuring tumor blood flow and for imaging tumor vascularity. Ease of use and real-time imaging capability make breast ultrasound a method of choice for guiding breast biopsies and other interventional procedures. Breast ultrasound is used in many forms. B-mode is the most common form of imaging for the breast, although compound imaging and harmonic imaging are being increasingly applied to better visualize breast lesions and to reduce image artifacts. These developments, together with the formulation of a standardized lexicon of solid mass features, have improved the diagnostic performance of breast ultrasound. Several approaches that are currently being investigated to further improve performance include: (1) computer-aided-diagnosis; (2) the assessment of tumor vascularity and tumor blood flow with Doppler ultrasound and contrast agents; and (3) tissue elasticity imaging. In the future, ultrasound will play a greater role in differentiating benign from malignant masses and in the diagnosis of breast cancer.

Quantitative Vascularity of Breast Masses by Doppler Imaging: Regional Variations and Diagnostic Implications

Seventy‐four biopsy proven breast masses were imaged by color and power Doppler imaging to evaluate vascular pattern of malignant and benign breast masses. The images were analyzed for vascularity. The measurements were made over the entire mass as well as regionally at its core, at its periphery, and in the tissue surrounding it. The surgical specimens were analyzed for microvessel density. The diagnostic performance of Doppler sonographic vascularity indices was evaluated by receiver operating characteristic analysis. The malignant masses were 14 to 54% more vascular than the benign masses. Both types of masses were more vascular by ultrasonography than the tissue surrounding them. Whereas benign masses were 2.2 times more vascular than the surrounding tissue, the malignant masses were 5.0 times more vascular. In a subset of patients the regional vascularity at the core, periphery, and surrounding tissue by Doppler imaging exhibited a strong correlation (R2 > 0.9) with the corresponding histologic microvessel density measurements. Although the malignant masses exhibited a strong gradient in vascularity, core > periphery > surrounding tissue, the benign masses had relatively uniform distribution of vascularity. The area under the receiver operating characteristic curve (A(Z)) for the Doppler indices ranged from 0.56 +/‐ 0.07 to 0.65 +/‐ 0.07. A nonlinear analysis including age‐specific values of Doppler indices improved the diagnostic performance to A(Z) = 0.85 +/‐ 0.06. In conclusion, quantitative Doppler imaging when used in combination with a nonlinear rule‐based approach has the potential for differentiating between malignant and benign masses.

Sonoluminescence of argon saturated alkali metal salt solutions as a probe of acoustic cavitation

Emission from argon saturated aqueous alkali metal salt solutions is observed during insonation at 460 kHz. It is postulated to arise from de‐excitation of excited alkali metal atoms formed by free radical reduction processes. In addition to the emission resonance lines, diffuse bands are observed at ∼554 nm and ∼740 nm for Na and K, respectively. The latter are due to emission from alkali metal–argon exciplexes and are known to occur when mixtures of alkali metal vapor and argon are rapidly compressed. An estimate of the cavitational temperatures and pressures is obtained by comparison of experimental emission band parameters with those derived theoretically.

A Review of Low-Intensity Ultrasound for Cancer Therapy

The literature describing the use of low-intensity ultrasound in four major areas of cancer therapy-sonodynamic therapy, ultrasound-mediated chemotherapy, ultrasound-mediated gene delivery and anti-vascular ultrasound therapy-was reviewed. Each technique consistently resulted in the death of cancer cells, and the bio-effects of ultrasound were attributed primarily to thermal actions and inertial cavitation. In each therapeutic modality, theranostic contrast agents composed of microbubbles played a role in both therapy and vascular imaging. The development of these agents is important as it establishes a therapeutic-diagnostic platform that can monitor the success of anti-cancer therapy. Little attention, however, has been given either to the direct assessment of the mechanisms underlying the observed bio-effects or to the viability of these therapies in naturally occurring cancers in larger mammals; if such investigations provided encouraging data, there could be prompt application of a therapy technique in the treatment of cancer patients.

Measurement of the acoustic nonlinearity parameter B/A in human tissues by a thermodynamic method

A thermodynamic method for measuring the acoustic nonlinearity parameter B/A in tissues is presented. It is based on the measurement of change in phase velocity as a function of time as the hydrostatic pressure of the sample is quickly reduced from a known value. This technique circumvents the effect of the attenuation in the medium and does not require a prior knowledge of the thermodynamic parameters of the tissues. The method is used to estimate nonlinearity parameters for normal and malignant tissues in the temperature range 20 degrees to 37 degrees C. The values and the temperature dependence of these parameters are found to vary with the nature of the tissues.