An important goal in cancer chemotherapy is to sensitively and quantitatively monitor the response of individual patients' tumors to successful, or unsuccessful, therapy so that regimens can be altered iteratively. Currently, tumor response is monitored by frank changes in tumor morphology, yet these markers take long to manifest and are not quantitative. Recent studies suggest that the apparent diffusion coefficient of water (ADCw), measured noninvasively with magnetic resonance imaging, is sensitively and reliably increased in response to successful CTx. In the present study, we investigate the combination chemotherapy response of human breast cancer tumor xenografts sensitive or resistant to Paclitaxel by monitoring changes in the ADCw. Our results indicate that there is a clear, substantial, and early increase in the ADCw after successful therapy in drug sensitive tumors and that there is no change in the ADCw in p-glycoprotein-positive tumors, which are resistant to Paclitaxel. The mechanism underlying these changes is unknown yet is consistent with apoptotic cell shrinkage and a concomitant increase in the extracellular water fraction.

Tumor pH is physiologically important since it influences a number of processes relevant to tumorigenesis and therapy. Hence, knowledge of localized pH within tumors would contribute to understanding these processes. The destructiveness, poor spatial resolution, and poor signal‐to‐noise ratio (SNR) of current technologies (e.g., microelectrodes, 31P magnetic resonance spectroscopy) have limited such studies. An extrinsic chemical extracellular pH (pHe) probe is described that is used in combination with 1H magnetic resonance spectroscopic imaging to yield pHe maps with a spatial resolution of 1 × 1 × 4 mm3. The principle of the technique is demonstrated on a phantom. Further data are shown to demonstrate its application in vivo, and results agree with previously reported pH values. The accuracy of the reported pH measurements is <0.1 pH units, as derived from a detailed analysis of the errors associated with the technique, the description of which is included. Magn Reson Med 41:743–750, 1999. © 1999 Wiley‐Liss, Inc.

The apparent diffusion coefficient (ADC), as measured by diffusion-weighted MRI, has proven useful in the diagnosis and evaluation of ischemic stroke. The ADC of tissue water is reduced by 30-50% following ischemia and provides excellent contrast between normal and affected tissue. Despite its clinical utility, there is no consensus on the biophysical mechanism underlying the reduction in ADC. In this work, a numerical simulation of water diffusion is used to predict the effects of cellular tissue properties on experimentally measured ADC. The model indicates that the biophysical mechanisms responsible for changes in ADC postischemia depend upon the time over which diffusion is measured. At short diffusion times, the ADC is dependent upon the intrinsic intracellular diffusivity, while at longer, clinically relevant diffusion times, the ADC is highly dependent upon the cell volume fraction. The model also predicts that at clinically relevant diffusion times, the 30-50% drop in ADC after ischemia can be accounted for by cell swelling alone when intracellular T 2 is allowed to be shorter than extracellular The idea to use NMR to measure diffusion was introduced by Torrey in 1956 (1). The clinical utility of diffusionweighted MRI (DWMRI) was realized in the early 1990s in the evaluation of ischemic stroke. Within minutes of onset, DWMRI exhibits hyperintensity in regions of the brain affected by acute stroke, while T 2 -weighted images remain unaffected. The apparent diffusion coefficient (ADC), a quantitative measure of the diffusion of water in tissue, decreases 30 -50% in ischemic regions of the brain (2,3). While these results have had significant clinical utility, there remains no consensus on the biophysical mechanisms causing the drop in ADC. Several mechanisms have been proposed, including increases in the intracellular volume fraction (IVF) (3), increased tortuosity of extracellular spaces (4), decreased membrane permeability (P mem ) (4), and decreases in the diffusion of water in the intracellular space (5,6). Because a large number of tissue parameters have been hypothesized to affect the ADC, mathematical models of water diffusion are useful to assess the role of each parameter on the ADC.In free diffusion, the signal from DWMRI decays exponentially with increasing b-value, and is characterized by the intrinsic diffusion coefficient, D. However, the diffusion of water in tissue is not free: water interacts with lipid membranes, macromolecules, and other cellular and extracellular constituents, causing the signal decay to deviate from the monoexponential decay observed in free diffusion (7,8). The ADC lumps all of these interactions into a single "apparent" diffusion coefficient, which is calculated by fitting the DWMRI signal to an exponential decay over a specific range of b-values, typically between 0 and 1000 sec/mm 2 . Therefore, the ADC provides little indication of the specific biophysical mechanisms contributing the DWMRI signal decay. Other analyses of diffusion fit the non-monoexponential signa...

For many anticancer therapies, it would be desirable to accurately monitor and quantify tumor response early in the treatment regimen. This would allow oncologists to continue effective therapies or discontinue ineffective therapies early in the course of treatment, and hence, reduce morbidity. This is especially true for second-line therapies, which have reduced response rates and increased toxicities. Previous works by others and ourselves have shown that water mobility, measured by diffusion-weighted magnetic resonance imaging (DW-MRI), increases early in tumors destined to respond to therapies. In the current communication, we further characterize the utility of DW-MRI to predict response of prostate cancer xenografts to docetaxel in SCID mice in a preclinical setting. The current data illustrate that tumor volumes and secreted prostate-specific antigen both respond strongly to docetaxel in a dose-responsive manner, and the apparent diffusion coefficient of water (ADC(w)) increases significantly by 2 days even at the lowest doses (10 mg/kg). The ADCw data were parsed by histogram analyses. Our results indicate that DW-MRI can be used for early detection of prostate carcinoma xenograft response to docetaxel chemotherapy.

Numerous pre-clinical and clinical reports have demonstrated that the MRI-measured apparent diffusion coefficient of water (ADC) increases early in the response to a wide variety of anti-cancer therapies. It has been proposed that this increase in ADC generally results from an increase in the tumor extracellular volume fraction leading to a greater degree of unrestricted water motion. Furthermore, an increase in extracellular volume has been ascribed to the cell shrinkage that occurs early in the process of programmed cell death. However, other modes of death can be initiated soon after beginning therapy. These other modes of death include mitotic catastrophe and necrosis, and may also involve changes in the fraction of water with unrestricted motion. This work examines whether MRI-measured ADC is altered in response to therapies that induce cell death via non-apoptotic mechanisms and correlates ADC changes with cell death modalities regionally within the tumor. Apoptotic responses were limited to the tumor periphery in apoptosis-proficient tumors. Apoptosis was not observed in deficient tumors. Mitotic catastrophe was observed after treatment at the periphery and deeper into the tumor. Necrosis was the predominant response in the center of the tumor. ADC changes were moderate in the periphery and larger in the center. The results indicate that early and significant changes in ADC can occur in concert with mitotic catastrophe and lytic necrosis in the absence of apoptosis. Hence, changes in ADC may be a generalized measure of cytotoxic response to chemotherapy.