Hon Yu

MRI evaluation of pathologically complete response and residual tumors in breast cancer after neoadjuvant chemotherapy

This study investigated the role of magnetic resonance imaging (MRI) in evaluation of pathologically complete response and residual tumors in patients who were receiving neoadjuvant chemotherapy (NAC) for both positive and negative HER‐2 breast cancer.

Correlation of dynamic contrast enhancement MRI parameters with microvessel density and VEGF for assessment of angiogenesis in breast cancer

To investigate the association between parameters obtained from dynamic contrast enhanced MRI (DCE‐MRI) of breast cancer using different analysis approaches, as well as their correlation with angiogenesis biomarkers (vascular endothelial growth factor and vessel density).

In vivo quantification of optical contrast agent dynamics in rat tumors by use of diffuse optical spectroscopy with magnetic resonance imaging coregistration

We present a study of the dynamics of optical contrast agents indocyanine green (ICG) and methylene blue (MB) in an adenocarcinoma rat tumor model. Measurements are conducted with a combined frequency-domain and steady-state optical technique that facilitates rapid measurement of tissue absorption in the 650-1000-nm spectral region. Tumors were also imaged by use of contrast-enhanced magnetic resonance imaging (MRI) and coregistered with the location of the optical probe. The absolute concentrations of contrast agent, oxyhemoglobin, deoxyhemoglobin, and water are measured simultaneously each second for approximately 10 min. The differing tissue uptake kinetics of ICG and MB in these late-stage tumors arise from differences in their effective molecular weights. ICG, because of its binding to plasma proteins, behaves as a macromolecular contrast agent with a low vascular permeability. A compartmental model describing ICG dynamics is used to quantify physiologic parameters related to capillary permeability. In contrast, MB behaves as a small-molecular-weight contrast agent that leaks rapidly from the vasculature into the extravascular, extracellular space, and is sensitive to blood flow and the arterial input function.

Serial MRI after experimental febrile seizures: Altered T2 signal without neuronal death

Whereas most febrile seizures (FSs) carry a benign outcome, a subpopulation of individuals with prolonged FSs are at risk for later temporal lobe epilepsy. Signal changes on magnetic resonance imaging (MRI) may provide early markers for changes in neuronal integrity that may promote epileptogenesis in such individuals. Here, we used serial MRIs, obtained before and at several time points after experimental prolonged FSs, to determine the prevalence and distribution of signal changes on T2‐weighted images and to investigate the pathological substrates leading to these changes. Seventy‐five percent of immature rats with experimental prolonged FSs had abnormal T2 signal enhancement at 24 hours, and 87.5% at 8 days after the seizures. The altered T2 values involved the dorsal hippocampus (75%), the piriform cortex (87.5%), and the amygdala (25%). However, these changes were not accompanied by evidence of neuronal injury or death in these regions, as assessed using the Fluoro‐Jade method. Thus, experimental prolonged FSs lead to relatively frequent abnormal MRI signal in “temporal lobe” structures. Although these changes do not signify cell death, they may denote pathological cellular processes that promote epileptogenesis. Ann Neurol 2004

Quantification of Choline-containing Compounds in Malignant Breast Tumors by 1H MR Spectroscopy Using Water as an Internal Reference at 1.5 T

The quantification of choline-containing compounds (Cho) in breast tumors by proton MR spectroscopy (1H-MRS) has been of great interest because such compounds have been linked to malignancy. In this study, an internal reference method for the absolute quantification of Cho metabolite in malignant breast tumors was presented using a clinical 1.5xa0T scanner. We performed in vitro measurements to examine the accuracy of absolute quantification using four phantoms of known choline chloride concentrations. There was a high correlation between the calculated concentrations by MRS and the known concentrations (r2 > 0.98). We applied the technique to in vivo breast study conducted on 45 patients with biopsy-confirmed breast cancer. After T1 and T2 relaxation times were corrected, the Cho levels in this work had a range of 0.76 – 21.20xa0mmol/kg from 34xa0MR spectra of 32 patients with malignant breast lesions. This result was rather consistent with the previously published value (i.e., 1.38 – 10xa0mmol/kg, Bolan et al. in Magn Reson Med 50:1134–1143, 2003). Therefore, we conclude that the internal method using the fully relaxed water as a reference could be used for quantifying Cho metabolite accurately in breast cancer patients using a clinical 1.5xa0T scanner.

Coregistration of diffuse optical spectroscopy and magnetic resonance imaging in a rat tumor model

We report coregistration of near-infrared diffuse optical spectroscopy (DOS) and magnetic resonance imaging (MRI) for the study of animal model tumors. A combined broadband steady-state and frequency-domain apparatus was used to determine tissue oxyhemoglobin, deoxyhemoglobin, and water concentration locally in tumors. Simultaneous MRI coregistration provided structural (T2-weighted) and contrast-enhanced images of the tumor that were correlated with the optical measurements. By use of Monte Carlo simulations, the optically sampled volume was superimposed on the MR images, showing precisely which tissue structure was probed optically. DOS and MRI coregistration measurements were performed on seven rats over 20 days and were separated into three tumor tissue classifications: viable, edematous, and necrotic. A ratio of water concentration to total hemoglobin concentration, as measured optically, was performed for each tissue type and showed values for edematous tissue to be greater than viable tissue (1.2 +/- 0.49 M/microM versus 0.48 +/- 0.15 M/microM). Tissue hemoglobin oxygen saturation (StO2) also showed a large variation between tissue types: viable tissue had an optically measured StO2 value of 61 +/- 5%, whereas StO2 determined for necrotic tissue was 43 +/- 6%.

Congruent MRI and Near-infrared Spectroscopy for Functional and Structural Imaging of Tumors

We present a combined near-infrared diffuse optical spectroscopy (DOS) and Magnetic Resonance Imaging (MRI) system for the study of animal model tumors. Acombined broadband steady-state and frequency domain optical spectroscopy apparatus was integrated with the MRI. The physiological properties of tissue rendered by MRI, including vascular volume fraction and water, were compared with chromophore concentrations as determined from the parameters obtained by optical measurements. DOS measurements provided oxyhemoglobin, deoxy-hemoglobin, and water concentration locally in tumors. A method for coregistration of the information obtained by both modalities was developed. Using Monte Carlo simulations, the optically sampled volume was superimposed on the MR images, illustrating which tissue structure was probed optically. Finally, two optical contrast agents, indocyanine green (ICG) and methylene blue (MB), were employed and their kinetics were measured by DOS system from different locations on the tumor and compared with Gd-DTPA enhancement maps obtained from MRI.

Background parenchymal enhancement in the contralateral normal breast of patients undergoing neoadjuvant chemotherapy measured by DCE-MRI.

The purpose of this study was to analyze background parenchymal enhancement (BPE) in the contralateral normal breast of cancer patients during the course of neoadjuvant chemotherapy (NAC). Forty-five subjects were analyzed. Each patient had three MRIs, one baseline (B/L) and two follow-up (F/U) studies. The fibroglandular tissue in the contralateral normal breast was segmented using a computer-assisted algorithm. Based on the segmented fibroglandular tissue, BPE was calculated. BPE measured in baseline (B/L) and follow-up (F/U) MR studies were compared. The baseline BPE was also correlated with age and compared between pre/peri-menopausal (<55 years old) and post-menopausal women (≥55 years old). The pre-treatment BPE measured in B/L MRI was significantly higher in women <55 years old than in women ≥55 years old (20.1%±7.4% vs. 12.1%±5.1%, p≤0.01). A trend of negative correlation between BPE and age was noted (r=-0.29). In women <55years old, BPE at F/U-1 (18.8%±6.9%) was decreased compared to B/L, and was further decreased in F/U-2 (13.3%±5.7%) which was significant compared to B/L and F/U-1. In women ≥55 years old, no significant difference was noted in any paired comparison among B/L, F/U-1 and F/U-2 MRI. A higher baseline BPE was associated with a greater reduction of BPE in F/U-2 MRI (r=0.73). Our study showed that younger women tended to have higher BPE than older women. BPE was significantly decreased in F/U-2 MRI after NAC in women <55 years old. The reduction in BPE was most likely due to the ovarian ablation induced by chemotherapeutic agents.

Inhibition of thrombosis in melanoma allografts in mice by endogenous mast cell heparin.

An unexplained paradox of malignant melanoma is the apparent failure of the blood within the tumor to clot despite the presence of multiple factors that should promote blood clotting. Here we present histochemical evidence that human and murine melanomas are extensively infiltrated by abundant mast cells. Because mast cells contain the natural anticoagulant heparin, the present studies were aimed at defining the role of mast cell heparin in preventing the blood from clotting within B16 melanoma grafts in C57BL/6 J mice. Mice bearing B16 melanoma grafts were treated with non-specific or specific inhibitors of mast cell heparin (protamine or heparinase, respectively). After the drug treatment there was histologic and functional evidence of selective thrombosis of the blood vessels within the protamine and heparinase treated melanoma grafts. A similar, high degree of thrombosis was also observed in B16 tumors grown in transgenic NDST-2 knockout mice bearing a targeted disruption in the gene coding for mast cell heparin synthesis. The tumors grown in the protamine-treated animals were significantly smaller than the tumors from control (untreated mice). By contrast, the tumors treated with heparinase or grown in the NDST-2 knockout mice were significantly larger than the tumors from control (untreated) mice. We conclude that the intrinsic procoagulant properties of malignant melanoma are neutralized in vivo by the anticoagulant properties of endogenous heparin produced by mast cells that naturally infiltrate the tumor. Our results also suggest that thrombosis and hemostasis within melanoma may play a complex role in modulating the growth of the tumor.

A Longitudinal Study of Radiation-Induced Changes in Tumor Vasculature by Contrast-Enhanced Magnetic Resonance Imaging

Abstract Yu, H., Su, M-Y., Wang, Z. and Nalcioglu O., A Longitudinal Study of Radiation-Induced Changes in Tumor Vasculature by Contrast-Enhanced Magnetic Resonance Imaging. Radiat. Res. 158, 152–158 (2002). Dynamic contrast-enhanced MRI with two different-sized contrast agents, Gd-DTPA and Gadomer-17, was used to study the effects of radiation on the pharmacokinetics of the paramagnetic enhancement of water relaxation in the rat R3230 AC adenocarcinoma tumor model. The kinetics of enhancement was analyzed by a two-compartment pharmacokinetic model to derive parameters related to vascular volume (Vb) and permeability (K2). Rats implanted with tumors were divided into two groups; one received 5 Gy and the other received 20 Gy 137Cs γ rays. Sequential dynamic contrast-enhanced MRI studies were performed, one before irradiation, one at day 1 after irradiation, and another at day 3 after irradiation, to investigate the effect of the radiation dose and the changes that occurred over time. The analysis was performed on a pixel-by-pixel basis to study the heterogeneity within the tumor. The pixel distribution profiles of Vb and K2 from each tumor were obtained to assess the regional radiation-induced effects on vascular volume and permeability. No significant change in vascular volume was detected with either Gd-DTPA or Gadomer-17 after irradiation of the tumor; however, a small dependence of K2 on the radiation dose was observed. After low-dose (5 Gy) irradiation, the mean value of K2 decreased by 46% at day 1 compared to the baseline, presumably due to cell swelling, and decreased further by 67% from the baseline on day 3. When the dose was increased to 20 Gy, the mean value of K2 measured with Gadomer-17 did not show any significant changes at either day 1 or day 3 after irradiation. The value of K2 measured with Gd-DTPA did not show any significant changes after either the low or the high radiation dose.