Enhancement of fluorouracil uptake in human colorectal and gastric cancers by interferon or by high-dose methotrexate: An in vivo human study using noninvasive (19)F-magnetic resonance spectroscopy.

PURPOSE: To study whether two modulators, high-dose methotrexate (MTX) and interferon alfa-2a (IFNalpha-2a) will alter the intratumoral pharmacokinetics of fluorouracil (5-FU). PATIENTS AND METHODS: Five patients, two with gastric cancer and three with colorectal cancer, who had metastatic tumor nodules in their livers were studied dynamically in vivo after 5-FU injection. In a magnetic resonance imaging unit, noninvasive (19)F-magnetic resonance spectroscopy (MRS) was used to detect (19)F signals from 5-FU and its metabolites. RESULTS: The intratumoral half-life (t(1/2)) of 5-FU in these tumors ranged from 18.8 minutes to 42.3 minutes. Four of the five patients exhibited increases in the t(1/2) of 5-FU after intravenous (IV) administration of MTX or IFNalpha-2a. In the two patients with gastric cancer who received IV high-dose MTX followed by IV 5-FU, increases were seen in either the total t(1/2) of 5-FU (41.8%) or in the t(1/2) of the alpha phase (150%). In the three patients with colorectal cancer who received IV IFNalpha-2a followed by IV 5-FU, the two patients with partial responses had increases in the t(1/2) of 5-FU of 41% and 30.2%, whereas the nonresponder had a nonsignificant increase (5.6%) in the t(1/2) of 5-FU. CONCLUSIONS: These results document that the in vivo modulation of the tumoral pharmacokinetics of 5-FU can be measured noninvasively by (19)F-MRS and suggest that such information correlates with subsequent clinical outcomes. The findings also indicate that IFNalpha-2a and high-dose MTX can increase the intratumoral 5-FU in some patients. Such information, obtained prospectively in vivo, may assist in better individual cancer patient management and in developing novel drug combinations.

Physics and instrumentation for imaging in-vivo drug distribution.

Several imaging methods are currently available to measure drugs noninvasively. Of these, two techniques are today central to such measurements: nuclear imaging and magnetic resonance imaging/spectroscopy (MRI and MRS). While other methods, such as optical techniques, are rapidly gaining in interest, they have not yet attained the degree of development that makes them effective in measuring drugs in living systems, except in a small number of examples. The following introduction provides some basic elements of the potential and the limitations of both nuclear imaging and MRI/MRS techniques, methods that will be used in the studies described in the articles in this issue. However, and for those desiring to gain a better understanding of both methods, the reader is advised to consult much more extensive reviews and books describing such methods. A suggested list of books and articles on Nuclear Imaging and MRI/MRS is given.

19F-MRS studies of fluorinated drugs in humans.

The use of 19F-NMR as a noninvasive probe to measure directly the pharmacokinetics of drugs at their target (effector) site(s) is illustrated in this article by human studies with 5-fluorouracil (5-FU). This drug, and several of its metabolites, have been measured in vivo in animals and in patients using standard clinical MRI systems. Using a pharmacokinetic imaging approach the parameter that can be measured most readily is the tumoral t(1/2) of 5-FU. Patients whose tumoral t(1/2) of 5-FU is equal to/greater than 20 min are designated as "trappers", and those whose tumoral t(1/2) of 5-FU is less are nontrappers. Trapping of 5-FU in tumors is a necessary, albeit not a sufficient condition, for response. Problems associated with the technical aspects of these measurements have been discussed, as well as how modulators and other agents will affect the tumoral t(1/2) of 5-FU. The rationale for the biological processes underlying the fate of 5-FU in humans has been illustrated with the use of a 12 compartment model, where several of the steps have been discussed and the consequences of their inhibition/stimulation related to the noninvasive studies that can be performed with modulators of the action of 5-FU. These 19F-NMR studies have now been extended to other fluoropyrimidines, some of which are prodrugs of 5-FU, and others where the fluorine atoms are on the ribose ring. These studies also reveal information that has both scientific and clinical significance. The studies presented here illustrate some of the potential and some of the usefulness of 19F-MRS in patient management and in drug development. It is a technique that has proven itself.

Quantitative multiple sclerosis plaque assessment with magnetic resonance imaging. Its correlation with clinical parameters, evoked potentials, and intra-blood-brain barrier IgG synthesis.

Magnetic resonance imaging (MRI) of the cerebrum, cerebellum, brain stem, and upper cervical cord was performed in 62 individuals with clinically definite chronic, progressive multiple sclerosis (MS). The total area of MRI-demonstrated lesions was measured from film enlargements for each region using an interactive image analysis system. While the MRI was abnormal in 60 (97%) of 62 patients, the visual-evoked potentials in 51 (85%) of 60 patients, the brain stem auditory-evoked potentials (BAEPs) in 24 (46%) of 52 patients, and the somatosensory-evoked potentials (SSEPs) in 45 (89%) of 54 patients, an abnormal intra-blood-brain barrier (BBB) IgG synthesis rate, IgG oligoclonal bands, or both were found in all 62 patients. The total area of MRI abnormality in the cerebrum was significantly correlated only with the intra-BBB IgG synthesis rate, abnormal visual-evoked potentials, impaired performance on the Symbol Digit Modalities Test (SDMT), and one test of standing duration in the quantitative examination of neurologic function (QENF). The brain stem lesion area correlated with the Kurtzke expanded disability status scale and brain stem functional systems score, the ambulation index, abnormal BAEPs, and impaired performance on the SDMT as well as multiple tests of upper and lower extremity function in the QENF. The cerebellar lesion area correlated with impaired performance on the SDMT and primarily upper extremity testing in the QENF.(ABSTRACT TRUNCATED AT 250 WORDS)

Magnetic resonance imaging of prostate cancer.

Over the past 10 years, dramatic developments in hardware and software have made magnetic resonance imaging a very powerful diagnostic tool for imaging body organs. In this review, the technique as it applies to prostate imaging is discussed, and the literature is reviewed to provide an overview of the current status of prostate magnetic resonance imaging as a tool for diagnosis and staging of prostate cancer.

Nuclear magnetic resonance imaging in detecting and staging prostatic cancer.

Thirteen patients were examined for grade, stage, and extent of their prostatic cancer, utilizing nuclear magnetic resonance imaging (MRI) and clinical workup for metastases. Of these 13 patients, 12 had known prostatic cancer proved by needle biopsy or by pathologic examination of transurethral prostatectomy tissue. Five of these patients underwent radical surgery allowing further correlation of clinical findings and MRI data with the surgical pathologic findings. MRI of the prostate was found to be a sensitive modality in detecting prostatic carcinoma and showing extension of disease in some cases. Also, in some cases it was not always possible to differentiate between prostatic carcinoma and benign prostatic hyperplasia with MRI.

Magnetic resonance imaging in acoustic neuroma diagnosis.

Magnetic resonance imaging (MRI) is capable of providing excellent images of the contents of the internal auditory canal and cerebellopontine angle. In order to determine whether MRI is comparable to air contrast computed tomography in the diagnosis of small acoustic neuromas, 44 patients with suspected retrocochlear disease were studied with both CT and MRI. Twenty-one lesions were identified successfully with MRI and CT. The size of the tumors ranged from 4 mm to 5 cm. In twenty-three nontumor patients the normal audiovestibular nerve bundles were well visualized. Air contrast CT, on the other hand, was falsely positive in two cases. The results of this study indicate that MRI is suitable as the primary anatomic investigation in patients suspected of having retrocochlear lesions. It has the advantages of being highly reliable as well as free of ionizing radiation and the need for invasive procedures. The expense of MRI compares favorably with that of combined intravenous and gas contrast CT.

Blood flow: magnetic resonance imaging.

The appearance of flowing fluid has been evaluated in several clinical situations using a flow phantom, computer simulation, and clinical magnetic resonance (MR) images. Unsaturated protons just entering the imaging volume can emit a strong signal relative to the partially saturated adjacent tissue ("flow-related enhancement"). Slow laminar flow in veins can be distinguished on the basis of a stronger second echo due to rephasing effects ("even echo rephasing"). Synchronization of the cardiac cycle and the MR pulsing sequence produces increased signal in sections acquired during diastole ("diastolic pseudogating"). Intraluminal signal is shown to decrease as velocity is increased ("high velocity signal loss"). Onset of turbulence causes further loss of signal. Direction of flow oblique to the imaging plane can be predicted on the basis of decreased upstream and increased downstream signal.

NMR even echo rephasing in slow laminar flow.

In nuclear magnetic resonance (NMR) imaging, flowing fluids possess several unusual properties not found in stationary materials. One of these is the strong signal emitted during slow flow by unsaturated protons just entering the imaging volume. Another is the observation that even echoes of a multiple spin-echo train have higher intensity than the odd. The two phenomena have not previously been distinguished in the NMR imaging literature and the term "paradoxical enhancement" has been applied to both. In this communication we consider the conditions under which such a phenomenon occurs, derive general mathematical relationships, and show clinical examples in which an understanding of spin-echo rephasing is especially useful.

Non-invasive 19F-NMRS of 5-fluorouracil in pharmacokinetics and pharmacodynamic studies.

Knowledge of the exact dose and rate at which an antitumor agent is delivered to its target site is postulated to be crucial to proper patient management. It is now possible to obtain such information using non-invasive 19F-NMRS (nuclear magnetic resonance spectroscopy) following the administration of 5-fluorouracil (5-FU). We have performed such studies in 103 patients with breast, colorectal and other tumors. Measurable 19F signals were detected in 99 of these patients (92.5%). Estimation of the tumoral t1/2 of 5-FU in these patients revealed that 51 of them (51.5%) exhibited a tumoral t1/2 greater than 20 min, a value we had characterized as indicating drug trapping in the tumor. Of these patients, 46 who received regimen bolus 5-FU 600 mg/m2 with leucovorin for their treatment have been evaluated. In these patients, the association between trapping and response remains very high (p<.000001). None of the non-trappers responded to chemotherapy, whereas 70% of the evaluable trappers responded. Details are presented here on the methodology of NMRS data acquisition and on their pharmacokinetic analysis. The potential mechanisms underlying the trapping effect appear to be predicated primarily on transport processes. Suggestions are presented on how such pharmacokinetic imaging studies may extend both our understanding of the mechanism of action of 5-FU, and how they could be used to optimize patient treatment.

Infantile cerebellar atrophy.

We describe a family whose members have a dominantly inherited, early-onset, nonprogressive syndrome that includes spontaneous upbeating nystagmus and mild gait ataxia. Magnetic resonance imaging showed localized atrophy of the cerebellar vermis. Several families described in the literature resemble our family but differ in mode of inheritance, age at onset, rate of progression, or clinical findings. We believe this family represents a unique type of inherited early-onset atrophy of the cerebellar vermis.

The appearance of rapidly flowing blood on magnetic resonance images.

The appearance of rapidly flowing blood on imaging (MRI) was evaluated using flow phantoms and dye infusion experiments. Laminar flow can be maintained at high velocities in small-diameter vessels. Under such conditions, flow-related enhancement may be observed several slices into a multislice imaging volume. Decreasing cross-sectional area of the unsaturated protons in the midstream is noted on slices further removed from the entry surface. As the velocity increases, turbulence occurs. The increased random motion of the protons causes loss of intensity on the first-echo image, although rephasing with increased intensity can be noted on the second-echo image. The flow pattern of a simple intraluminal obstruction is demonstrated by MRI and dye infusion experiments. Rephasing is noted within the eddy downstream from the obstruction. Clinical examples of the phantom findings are shown and applications are discussed.

Comparison of CT and MR in 400 patients with suspected disease of the brain and cervical spinal cord.

Magnetic resonance imaging (MR) (0.35 T) and computed tomography (CT) were compared in 400 consecutive patients with suspected disease of the brain and cervical spinal cord. Of 325 positive diagnoses, MR detected abnormality while CT was normal in 93; MR was more specific in 68; MR and CT gave equivalent information in 129; CT was more specific in 32; and CT was positive while MR was normal in 3. MR was superior to CT in detection of multiple sclerosis, subcortical arteriosclerotic encephalopathy, posterior fossa infarcts and tumors, small extra-axial fluid collections, and cervical syringomyelia. CT was preferable in evaluation of meningiomas and separation of tumor from edema. Using available sequence parameters, MR missed 3 1-cm calcified meningiomas which were clearly seen on CT. CT takes less time and may be preferable in patients with acute trauma as well as very young or elderly individuals. Thus the two studies should be considered complementary.

Endorectal surface coil MR imaging of prostatic carcinoma with the inversion-recovery sequence.

The value of inversion-recovery (IR) sequences in the diagnosis and staging of prostatic carcinoma with magnetic resonance (MR) imaging was studied. Twenty-six patients with carcinoma of the prostate were imaged at 1.5 T with an endorectal surface coil and with a variety of IR sequences and a set of spin-echo (SE) sequences for comparison. Ex vivo prostate specimens were imaged again at the same field strength. The two images were correlated with histologic sections. Cancer was identified with MR imaging in 96% of patients. Of the tumors more than 4 mm in diameter, 87% were identified on T2-weighted SE images, whereas only 26% were identified on IR images. However, IR images may be more useful in local staging of carcinoma. Gross capsular infiltration was present in only two patients; however, it was detectable (and excluded in five other patients) by means of IR images. It was not detectable on SE images. The high quality of images obtained with the endorectal coil was confirmed. The authors conclude that addition of the IR sequence to MR imaging with the endorectal coil may improve the usefulness of this examination.

Association of intratumoral pharmacokinetics of fluorouracil with clinical response.

In-vivo fluorine-19 nuclear magnetic resonance spectroscopy (NMRS) allows non-invasive, real-time, chemical identification of specific fluorinated compounds inside human tumours after administration of fluorouracil (5-fluorouracil). Kinetic measures of the administered drug and metabolites allow estimation of the tumoral half-life of fluorouracil. We studied 57 patients by 19F NMRS immediately after they had received 600 mg/m2 fluorouracil intravenously. Serial spectra were acquired with the surface coil positioned on the skin above the tumour. We defined an intratumoral half-life of fluorouracil of 20 min or more as indicating trapping of the drug, based on the blood half-life of 8-12 min. 19 patients had intratumoral half-lives indicating trapping of fluorouracil, 27 had half-lives less than 20 min, and 11 had no detectable fluorouracil in their tumours. 8 of 9 evaluable patients whose tumours showed trapping had partial responses to chemotherapy that included fluorouracil compared with only 2 of 25 patients whose tumours did not trap the drug (p = 0.000021). 19F NMRS can identify patients likely to respond to chemotherapy with fluorouracil and could be used clinically to tailor optimum treatment.

Endolymphatic sac tumors: radiologic appearance.

PURPOSE: To evaluate the radiologic appearance of endolymphatic sac tumors (ELSTs). MATERIALS AND METHODS: Four patients with ELST underwent computed tomography (CT), and two of the four also underwent magnetic resonance (MR) imaging. Their radiologic studies were reviewed for characteristic findings of ELST. RESULTS: Retrolabyrinthine bone destruction was centered at the external aperture of the vestibular aqueduct in all four patients. CT showed irregular bone margins and prominent intratumoral bone in all four patients. At MR imaging, one tumor was almost homogeneous and isointense to gray matter with T1 weighting, and the other was heterogeneous and contained hyper-, hypo-, and isointense foci with T1 and T2 weighting. CONCLUSION: These radiologic changes may help distinguish ELSTs from other tumors of the temporal bone and posterior fossa.

Intratemporal vascular tumors: evaluation with CT.

Eleven patients each with a benign intratemporal vascular tumor (hemangioma or vascular malformation) were assessed with computed tomography (CT). Clinical, surgical, and histologic correlations were also available. On CT scans, most of the 11 tumors were smaller than 10 mm. Four occurred in or around the internal acoustic canal, six at the geniculate ganglion, and one at the posterior genu. The involved bone margins were often unsharp, and "honeycomb" bone or intratumoral bone spicules were sometimes present. Intratemporal vascular tumors cause profound nerve deficits despite their small size and must be resected early to salvage nerve function.

Intratemporal vascular tumors: detection with CT and MR imaging.

The diagnostic contributions of computed tomography (CT) and magnetic resonance (MR) imaging were compared in 12 patients with benign intratemporal vascular tumors (hemangioma or vascular malformation). The tumors included six in the internal acoustic canal and six in the geniculate ganglion region. Clinical and histologic correlations were made. Two of the six patients with tumors in the internal acoustic canal underwent CT, and both required gas cisternography to show the tumor. Five patients in that group underwent MR imaging, and all five studies showed the tumor. All six patients with geniculate ganglion tumors underwent CT. Results in one study were questionable, and five showed the tumor. Five patients in this group underwent MR imaging, but the MR findings were positive in only two cases. MR imaging should therefore be performed before CT in the evaluation of facial nerve dysfunction, as it demonstrated all tumors in the internal acoustic canal and some in the geniculate ganglion region. If MR findings are negative, CT should then be performed to rule out a possible geniculate ganglion lesion.