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Arvind P Pathak

Publications and source records attributed to Arvind P Pathak.

11 recordsLinked to original sources
PubMed2006

Magnetic resonance imaging of tumor physiology.

Cancer is one of the most mutable diseases known, exhibiting a superfluity and heterogeneity of molecular pathways that impart an almost chimerical nature to it. Exploiting these pathways for patient therapy demands an understanding of the physiology of tumors from the molecular to the systemic level. To this end, multiparametric functional and molecular imaging play a vital role in not only tracking delivery and efficacy of therapy, but also in discovering novel therapeutic targets. The plethora of available magnetic resonance (MR) contrast mechanisms, in conjunction with its superior dynamic functional range, bestow on magnetic resonance imaging (MRI) the potential to be a formidable tool in the noninvasive, in vivo, multilevel assessment of tumor physiology. This chapter begins with a description of the aberrant pathophysiology of tumors, including a description of tumor angiogenesis and how MRI affords us a window into such processes. Following a discussion of endogenous and exogenous contrast, a specific example of measuring a tumor's vascular parameters with a macromolecular contrast agent is considered. This is followed by a description of revolutionary developments in the molecular imaging of tumors with MRI and complementary modalities.

Animals↗
PubMed2005

Twist overexpression induces in vivo angiogenesis and correlates with chromosomal instability in breast cancer.

Aggressive cancer phenotypes are a manifestation of many different genetic alterations that promote rapid proliferation and metastasis. In this study, we show that stable overexpression of Twist in a breast cancer cell line, MCF-7, altered its morphology to a fibroblastic-like phenotype, which exhibited protein markers representative of a mesenchymal transformation. In addition, it was observed that MCF-7/Twist cells had increased vascular endothelial growth factor (VEGF) synthesis when compared with empty vector control cells. The functional changes induced by VEGF in vivo were analyzed by functional magnetic resonance imaging (MRI) of MCF-7/Twist-xenografted tumors. MRI showed that MCF-7/Twist tumors exhibited higher vascular volume and vascular permeability in vivo than the MCF-7/vector control xenografts. Moreover, elevated expression of Twist in breast tumor samples obtained from patients correlated strongly with high-grade invasive carcinomas and with chromosome instability, particularly gains of chromosomes 1 and 7. Taken together, these results show that Twist overexpression in breast cancer cells can induce angiogenesis, correlates with chromosomal instability, and promotes an epithelial-mesenchymal-like transition that is pivotal for the transformation into an aggressive breast cancer phenotype.

Animals↗
PubMed2005

Characterizing extravascular fluid transport of macromolecules in the tumor interstitium by magnetic resonance imaging.

Noninvasive imaging techniques to image and characterize delivery and transport of macromolecules through the extracellular matrix (ECM) and supporting stroma of a tumor are necessary to develop treatments that alter the porosity and integrity of the ECM for improved delivery of therapeutic agents and to understand factors which influence and control delivery, movement, and clearance of macromolecules. In this study, a noninvasive imaging technique was developed to characterize the delivery as well as interstitial transport of a macromolecular agent, albumin-GdDTPA, in the MCF-7 human breast cancer model in vivo, using magnetic resonance imaging. The transport parameters derived included vascular volume, permeability surface area product, macromolecular fluid exudate volume, and drainage and pooling rates. Immunohistochemical staining for the lymphatic endothelial marker LYVE-1 was done to determine the contribution of lymphatics to the macromolecular drainage. Distinct pooling and draining regions were detected in the tumors using magnetic resonance imaging. A few lymphatic vessels positively stained for LYVE-1 were also detected although these were primarily collapsed and tenuous suggesting that lymphatic drainage played a minimal role, and that the bulk of drainage was due to convective transport through the ECM in this tumor model.

Albumins↗
PubMed2004

Novel system for determining contrast agent concentration in mouse blood in vivo.

A method for measuring contrast agent concentration in blood was developed using a switchable RF tail coil to obtain MR signal from the mouse tail vein. The switchable RF coil was used to obtain quantitative high-resolution T1 maps of the tail in combination with a second coil used to obtain images from regions of interest in a mouse tumor model. The effect of flow rates on the T1 measurements was validated using a flow-phantom. Reliable estimates of blood T1 were obtained for flow rates up to 0.5 cm/sec in SCID mice. There was no significant difference between the in vivo tail coil measurements and in vitro blood sample relaxation rates of blood. The ability to measure the concentration of contrast agents in mouse blood in vivo is useful for several applications, such as obtaining quantitative values of tumor vascular volume and permeability, determining the effectiveness of drug delivery to tumors, or for detecting lymphatic drain.

Albumins↗
PubMed2004

Visualizing function in the tumor-associated lymphatic system.

The recent surge of interest in the lymphatic system can be attributed to two factors: the discovery of cytokines that induce the growth of new lymphatic capillaries and the identification of lymphatic endothelial-specific markers. In contrast to the above, there is a paucity of techniques for studying lymphatic function in vivo. This article reviews imaging and other techniques that allow the assessment of lymphatic function, particularly in the tumor microenvironment, and proposes novel solutions for probing the same in vivo.

Animals↗
PubMed2004

Characterization of a first-pass gradient-echo spin-echo method to predict brain tumor grade and angiogenesis.

BACKGROUND AND PURPOSE: No widespread clinical method provides specific information about the angiogenic characteristics of gliomas. We characterized blood volume and vascular morphologic parameters from combined gradient-echo (GE) and spin-echo (SE) MR imaging and assessed their relationship to tumor grade, a known correlate of glioma angiogenesis. METHODS: Simultaneous GE and SE echo-planar imaging was performed with bolus gadolinium administration (0.20-0.25 mmol/kg) in 73 patients with glioma. To diminish possible T1 changes due to contrast agent extravasation, a preload (0.05-0.10 mmol/kg) was administered before the study, and a postprocessing correction algorithm was applied. Image maps of total (GE) and microvascular (SE) relative cerebral blood volume (rCBV) and the mean vessel diameter (mVD) calculated from the ratio of GE and SE relaxation rate changes (DeltaR2*/DeltaR2) were compared with tumor grade. A nonparametric K nearest-neighbor decision rule was applied to determine if the combined data could be used to distinguish low-grade (I-II) from high-grade (III-IV) tumors on a per-patient basis. RESULTS: For whole tumors, significant correlations were found between GE rCBV and grade (P < .0001) and between mVD and grade (P = .0001) but not between SE rCBV and grade (P = .08). For areas of highest SE rCBV (microvascular hotspots), SE rCBV and tumor grade were significantly correlated (P = .0007). In terms of differentiation, 69% of low-grade tumors and 96% of high-grade tumors were correctly classified. CONCLUSION: Combined GE and SE MR imaging provides information consistent with neoplastic angiogenesis, demonstrating its potential to aid in optimizing treatments, categorizing lesions, and influencing patient care.

Adult↗
PubMed2003

The effect of brain tumor angiogenesis on the in vivo relationship between the gradient-echo relaxation rate change (DeltaR2*) and contrast agent (MION) dose.

PURPOSE: To determine in vivo if the susceptibility calibration factor for gradient-echo imaging (k(G)), which characterizes the relationship between the tissue T2* relaxation rate change (DeltaR2*) and tissue contrast agent concentration, is independent of tissue type and condition; in addition, to assess the consequences of such an assumption on the use of relative cerebral blood volume (rCBV) measurements as a direct index of tumor angiogenesis. MATERIALS AND METHODS: The DeltaR2* was measured as a function of monocrystalline iron oxide nanoparticles (MION) contrast agent dose in a rat brain tumor (9L gliosarcoma) model, the blood volume fraction independently measured, and k(G) calculated and compared for the normal gray matter, normal white matter, tumor, and contralateral brain. RESULTS: The k(G) was found to be the same for gray and white matter (P = 0.53), but statistically different for tumor compared to contralateral brain (P = 0.005) with k(G(Tumor) ) < k(G(Brain) ) CONCLUSION: The gradient-echo calibration factor, k(G), is the same for brain gray and white matter, but not the same for brain and tumor tissue. This difference may be attributed to the grossly different vascular morphology of tumors, dueto tumor angiogenesis, compared to normal brain and/or possibly differing blood rheological factors such as hematocrit. Consequently, the sensitivity to blood volume differences between tumor and normal brain tissue may be lessened when using gradient-echo susceptibility contrast agent methods.

Animals↗
PubMed2003

Antiangiogenic effects of dexamethasone in 9L gliosarcoma assessed by MRI cerebral blood volume maps.

Depending on dose, dexamethasone has been shown to inhibit or stimulate growth of rat 9L gliosarcoma and decrease the expression of vascular endothelial growth factor (VEGF), an important mediator of tumor-associated angiogenesis. We demonstrate, by constructing relative cerebral blood volume (rCBV) maps with MRI, that dexamethasone also decreases total blood volume while increasing microvascular blood volume in Fischer rats bearing intracranial 9L gliosarcoma. Animals were inoculated with 1 x 10(5) 9L gliosarcoma tumor cells. On days 10-14 after tumor cell inoculation, animals were intra-peritoneally injected with dexamethasone (3 mg/kg) over 5 days. MRI-derived gradient echo (GE) and spin-echo (SE) rCBV maps were created to demonstrate total vasculature (GE) and microvasculature (SE). After MRI studies were performed, the rat's vasculature was perfused with a latex compound. Total vessel volume and diameters were assessed by microscopy. Dexamethasone decreased the tumor-enhancing area of postcontrast T1-weighted images (P < 0.0001) and total tumor volume(P = 0.0085). In addition, there was a greater than 50% decrease in GE rCBV (total vasculature) (P = 0.007) as well as a significant decrease in total fractional blood volume, as validated by histology (P = 0.0007). Conversely, there was an increase in SE rCBV signal (microvasculature) in animals treated with dexamethasone (P = 0.05), which was consistent with microscopy (P < 0.0001). These data demonstrate that (1) dexamethasone selectively treats tumor vasculature, suggesting a vessel-size selective effect and (2) MRI-derived rCBV is a noninvasive technique that can be used to evaluate changes in blood volume and vascular morphology.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Extracellular acidification alters lysosomal trafficking in human breast cancer cells.

Cancer cells invade by secreting degradative enzymes, which are sequestered in lysosomal vesicles. In this study, the impact of an acidic extracellular environment on lysosome size, number, and distance from the nucleus in human mammary epithelial cells (HMECs) and breast cancer cells of different degrees of malignancy was characterized because the physiological microenvironment of tumors is frequently characterized by extracellular acidity. An acidic extracellular pH (pH(e)) resulted in a distinct shift of lysosomes from the perinuclear region to the cell periphery irrespective of the HMECs' degree of malignancy. With decreasing pH, larger lysosomal vesicles were observed more frequently in highly metastatic breast cancer cells, whereas smaller lysosomes were observed in poorly metastatic breast cancer cells and HMECs. The number of lysosomes decreased with acidic pH values. The displacement of lysosomes to the cell periphery driven by extracellular acidosis may facilitate exocytosis of these lysosomes and increase secretion of degradative enzymes. Filopodia formations, which were observed more frequently in highly metastatic breast cancer cells maintained at acidic pH(e), may also contribute to invasion.

Antigens, CD↗
PubMedDate not supplied

Decoupling of the hemodynamic and activation-induced delays in functional magnetic resonance imaging.

PURPOSE: The objective of this study was to develop a technique to decouple the hemodynamic delay from the task-induced delay on a voxel-by-voxel basis in functional magnetic resonance imaging (fMRI) data sets. Prior fMRI studies have reported variability in temporal delays of up to several seconds among activated voxels. It is currently assumed that this variability primarily arises from differences in the onset of task-induced activation, although the precise source of these delays has not been well characterized. Here, we hypothesize that the total delay during task activation can be modeled as a combination of neuronal (caused by differences in onset of neuronal firing), vasomotor (caused by flow changes during activation), and transit (caused by differences in the red blood cell arrival time) delays. METHOD: Subjects were scanned using a sequential dynamic susceptibility contrast (DSC) protocol during rest and fMRI of the motor cortex using a bilateral finger-tapping task. The total delay was determined using correlation coefficient analysis, whereas the intrinsic delay was determined from the DSC MRI. Subtraction of the transit delay from the corresponding total delay for each voxel yielded the task-induced delay. RESULTS: In all subjects, a transit delay of 2.3 (+/-1.1) seconds and a task-induced delay of 0.7 (+/-0.6) second was observed between voxels, which is in good agreement with reports in the literature using other techniques. These results demonstrate the feasibility of the DSC MRI for separating the hemodynamic and task-induced delays in fMRI studies. CONCLUSION: This approach has the potential to elucidate the temporal characteristics of the blood oxygenation level-dependent signal during fMRI as well as to further our understanding of the dynamics of the activation-induced signal in neuroimaging.

Adult↗