Elissa L. Kramer

Protective Effect of the Bispiperazinedione ICRF-187 against Doxorubicin-Induced Cardiac Toxicity in Women with Advanced Breast Cancer

Studies in animals suggest that the bispiperazinedione ICRF-187 can prevent the development of dose-related doxorubicin-induced cardiac toxicity. In a randomized trial in 92 women with advanced breast cancer, we compared treatment with fluorouracil, doxorubicin, and cyclophosphamide (FDC), given every 21 days, with the same regimen preceded by administration of ICRF-187 (FDC + ICRF-187). Patients were withdrawn from the study when cardiac toxicity developed or the cancer progressed. The mean cumulative dose of doxorubicin tolerated by patients withdrawn from study was 397.2 mg per square meter of body-surface area in the FDC group and 466.3 mg in the FDC + ICRF-187 group (no significant difference). Eleven patients on the FDC + ICRF-187 arm received cumulative doxorubicin doses above 600 mg per square meter, whereas one receiving FDC was able to remain in the study beyond this dose. Antitumor response rates were similar (FDC vs. FDC + ICRF-187, 3 vs. 4 complete responses; 17 vs. 17 partial responses; and 9.3 vs. 10.3 months to disease progression). Although myelosuppression was slightly greater in the FDC + ICRF-187 group, the incidence of fever, infections, alopecia, nausea and vomiting, or death due to toxicity did not differ between the groups. Cardiac toxicity was evaluated by clinical examination, determination of the left ventricular ejection fraction by multigated nuclear scans, and endomyocardial biopsy. In comparisons of the FDC group with the FDC + ICRF-187 group, clinical congestive heart failure was observed in 11 as compared with 2 patients; the mean decrease in the left ventricular ejection fraction was 7 vs. 1 percent when the cumulative dose of doxorubicin was 250 to 399 mg per square meter (P = 0.02), 16 vs. 1 percent at 400 to 499 mg (P = 0.001), and 16 vs. 3 percent at 500 to 599 mg (P = 0.003); and the Billingham biopsy score was 2 or more in 5 of 13 patients undergoing biopsy vs. none of 13 (P = 0.03). We conclude that ICRF-187 offers significant protection against cardiac toxicity caused by doxorubicin, without affecting the antitumor effect of doxorubicin or the incidence of noncardiac toxic reactions.

ICRF-187 Permits Longer Treatment With Doxorubicin in Women With Breast Cancer

PURPOSE To test potential protection by ICRF-187 against cumulative doxorubicin-dose-related cardiac toxicity, we conducted a randomized clinical trial in 150 women with advanced breast cancer. PATIENTS AND METHODS Patients received fluorouracil (5FU) 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days intravenously (IV) (control regimen, 74 patients), or the same regimen preceded by ICRF-187 1,000 mg/m2 IV (experimental regimen, 76 patients). RESULTS We previously reported that ICRF-187 in this dose and schedule provides cardiac protection and does not substantially alter the noncardiac toxicity or antitumor efficacy of the control regimen. In this updated analysis of the entire patient cohort, we provide additional support for these findings and demonstrate that patients in the ICRF-187 group received more cycles (median, 11) and higher cumulative doses (median, 500 mg/m2) of doxorubicin than patients in the control group (median, nine cycles, P less than .01; and 441 mg/m2, P less than .05). Twenty-six patients in the ICRF-187 group received doxorubicin doses of at least 700 mg/m2, and among them, 11 patients received 1,000 mg/m2 or more. Only three patients in the control group received doxorubicin doses of 700 mg/m2; the maximum dose administered to one patient in this group was 950 mg/m2. ICRF-187 cardiac protection was demonstrated by difference in incidence of clinical congestive heart failure (CHF; two patients in the ICRF-187 group v 20 in the control group; P less than .0001) and by differences in resting left ventricular ejection fraction (LVEF) determined by multigated radionuclide (MUGA) scan from baselines and that required patient removal from study (five patients in the ICRF-187 group had a decrease in LVEF to less than 0.45 or a decrease from the baseline LVEF of 0.20 or more v 32 in the control group; P less than .000001). Among the 30 patients who had an assessable endomyocardial biopsy at cumulative doxorubicin 450 mg/m2, none of 16 in the ICRF-187 group and six of 14 in the control group had a score of 2 (P less than .05). ICRF-187 cardiac protection was observed in patients with and without prior chest-wall radiation or other risk factors for developing doxorubicin cardiac toxicity. CONCLUSION By protecting against cumulative doxorubicin-induced cardiac toxicity, ICRF-187 permits significantly greater doses of doxorubicin to be administered to patients with greater safety.

The value of radionuclide angiography as a predictor of perioperative myocardial infarction in patients undergoing abdominal aortic aneurysm resection

To define the group of patients at high risk for myocardial infarction (MI) and death associated with abdominal aortic aneurysm repair, resting gated blood pool studies were obtained on 50 such aneurysm patients preoperatively. The results indicated that three groups could be distinguished among these patients by cardiac ejection fraction. Group I (n = 25) had preoperative ejection fractions ranging from 56% to 85%. None of the patients in group I suffered an acute perioperative MI. Group II (n = 20) comprised patients with ejection fractions ranging from 36% to 55%. There was a 20% incidence of MI in group II but no cardiac deaths. Group III included five patients with ejection fractions ranging from 27% to 35%. There was an 80% incidence of perioperative MI in these patients, with one cardiac death and one cardiac arrest. All perioperative MIs occurred within the first 48 hours after surgery. In addition there was a 50% incidence of perioperative MI among all those patients who were 80 years of age or older. These results indicate guidelines for the management of patients undergoing abdominal aortic aneurysm repair based on their preoperative ejection fraction. The data further suggest that the noninvasive gated blood pool method of determining ejection fraction may serve a more broadly useful function in helping to determine which of those patients about to undergo major surgical procedures are at high risk for perioperative MI.

Improving Specificity of Breast MRI Using Prone PET and Fused MRI and PET 3D Volume Datasets

MRI is a sensitive method for detecting invasive breast cancer, but it lacks specificity. To examine the effect of combining PET with MRI on breast lesion characterization, a prototype positioning device was fabricated to allow PET scans to be acquired in the same position as MRI scans—that is, prone. Methods: To test the hypothesis that fusion of 18F-FDG PET and MRI scans improves detection of breast cancer, 23 patients with suspected recurrent or new breast cancer underwent a routine whole-body PET scan, a prone PET scan of the chest, and a routine breast MRI scan. The attenuation-corrected prone PET and MRI datasets were registered twice by different operators. The fusion results were judged for quality by visual inspection and statistical analysis. A joint reading of the MRI and PET scans side by side and integrated images was performed by a nuclear medicine physician and a radiologist. Sensitivity and specificity of MRI and combined MRI and PET scans were calculated on the basis of pathology reports or at least 1 y of clinical and radiologic follow-up. Results: All fusions were verified to be well matched using specific anatomic criteria. A total of 45 lesions was assessed. Lesion size range was 0.6 to 10.0 cm. Of the 44 breasts examined, 29 were suspicious for cancer, of which 15 were found to be positive on surgical excision. In lesion-by-lesion analysis, sensitivity and specificity of MRI alone were 92% and 52%, respectively; after MRI and PET fusion, they were 63% and 95%, respectively. The positive predictive value and the negative predictive value for MRI alone were 69% and 85%, respectively; after MRI and PET fusion, they were 94% and 69%, respectively. Conclusion: Acquisition of prone PET scans using the new positioning device permitted acquisition of prone scans suitable for fusion with breast MRI scans. Fused PET and MRI scans increased the specificity of MRI but decreased the sensitivity in this small group of patients. Additional data are needed to confirm the statistical significance of these preliminary findings.

Quantitative determination of Gd-DTPA concentration in T1-weighted MR renography studies.

A method for calculating contrast agent concentration from MR signal intensity (SI) was developed and validated for T1‐weighted MR renography (MRR) studies. This method is based on reference measurements of SI and relaxation time T1 in a Gd‐DTPA‐doped water phantom. The same form of SI vs. T1 dependence was observed in human tissues. Contrast concentrations calculated by the proposed method showed no bias between 0 and 1 mM, and agreed better with the reference values derived from direct T1 measurements than the concentrations calculated using the relative signal method. Phantom‐based conversion was used to determine the contrast concentrations in kidney tissues of nine patients who underwent dynamic Gd‐DTPA‐enhanced 3D MRR at 1.5T and 99mTc‐DTPA radionuclide renography (RR). The concentrations of both contrast agents were found to be close in magnitude and showed similar uptake and washout behavior. As shown by Monte Carlo simulations, errors in concentration due to SI noise were below 10% for SNR = 20, while a 10% error in precontrast T1 values resulted in a 12–17% error for concentrations between 0.1 and 1 mM. The proposed method is expected to be particularly useful for assessing regions with highly concentrated contrast. Magn Reson Med 57:1012–1018, 2007.

A Versatile Functional–Anatomic Image Fusion Method for Volume Data Sets

We describe and validate a volumetric three-dimensional registration method, and compare it to our previously validated two-dimensional/three-dimensional method. CT/MRI and SPECT data from 14 patients were interactively fused using a polynomial warping technique. Registration accuracy was confirmed visually and by a nonsignificant F value from multivariate analysis of the transformed landmarks, a significant difference of the squared sum of intensity differences between the transformed/untransformed and the reference volume both at the 0.05 (p > 0.05) confidence level and an average 31% improvement of the correlation coefficient and cross correlation. For the two-dimensional/three-dimensional method, ROI center-to-center distance ranged from 1.42 to 11.32 mm (for liver) with an average of 6.13 mm ± 3.09 mm. The average ROI overlap was 92.51% with a 95% confidence interval of 90.20–96.88%. The new method is superior because it operates on the true three-dimensional volume. Both methods give good registration results, take 10 to 30 min, and require anatomic knowledge.

Evaluation of a Semiautomatic 3D Fusion Technique Applied to Molecular Imaging and MRI Brain/Frame Volume Data Sets

A generally applicable 3D fusion method was evaluated using molecular imaging and MRI volumetric data sets from 15 brain tumor patients with stereotactic frames attached to their skull. Point pairs, placed on the frame only, were chosen, polynomial warping coefficients were generated to map voxels from one coordinate space to the other. The MRI frame was considered the reference structure and the standard for “correct” registration. An ANOVA test (p > 0.05) confirmed the point pair choice to be consistent. The 95% confidence interval for the t-test showed the measured distance difference between the registered volumes was within one MRI voxel. A further experiment was conducted to independently evaluate the brain registration based on testing for consistency of randomly selected interior/exterior points. A t-test result (p < 0.05) showed that the consistency (i.e., both interior or both exterior) before and after volume registration were significantly different. This fusion method may be a viable alternative when other methods fail.

What causes diminished corticomedullary differentiation in renal insufficiency

To investigate whether the loss of corticomedullary differentiation (CMD) on T1‐weighted MR images due to renal insufficiency can be attributed to changes in T1 values of the cortex, medulla, or both.

Brain imaging in acquired immunodeficiency syndrome dementia complex

Human immunodeficiency virus (HIV) infections are accompanied by many different types of neurological complications. Opportunistic infections and neoplasms, particularly lymphoma, are often an underlying cause for these complications in patients with acquired immunodeficiency syndrome (AIDS). Frequently, these can be detected by cerebrospinal fluid (CSF) examination, double-dose contrast transmission computed tomography (CT), and/or magnetic resonance imaging (MRI). It has become apparent that the HIV itself is responsible for a significant percentage of neurological disease in the HIV-seropositive individual. The onset may be subtle and may occur before the onset of frank immunosuppression. Diagnosis of HIV encephalitis or AIDS dementia complex (ADC) is complicated by the frequent coexistence of opportunistic infections. Structural neuroimaging (CT or MRI) shows atrophy and in some case white matter abnormalities, but imaging-pathological correlation suggests that these modalities are relatively insensitive to the presence of HIV brain infection. Functional neuroimaging, both 18fluorodeoxyglucose positron emission tomography (PET) for evaluation of glucose metabolism and 123I iodoamphetamine or 99mTc-HMPAO single-photon emission computed tomography (SPECT) for evaluation of cerebral perfusion, can demonstrate abnormalities in the subcortical gray matter structures and the cerebral cortex in patients with ADC. These abnormalities may be observed early in the course of ADC even when MRI is negative and the patient is relatively asymptomatic. Also, PET and SPECT may be useful to follow progression of the dementia or response to therapy.

Prone mammoPET acquisition improves the ability to fuse MRI and PET breast scans.

Purpose: This study compared prone acquisition of PET scans with traditional supine acquisition to improve fusion of PET scans with MRI scans and improve evaluation of enhancing breast lesions detected on MRI. Materials and Methods: MRI breast scans are acquired in the prone position using a breast coil to allow the breasts to hang pendant. An apparatus was fabricated to allow prone acquisition of PET scans. Fused scans from 2 patients acquired both prone and supine were contrasted with those from 3 patients acquired supine only. All 5 MRI scans were acquired on standard scanners. The PET scans were acquired with a PET/CT unit using a low-dose CT scan for attenuation correction. The PET and MRI volumes were matched twice (using a semiautomated registration method) by different operators. The additional value of fusion was judged using reports from the original (nonfused) MRI and PET, joint rereading of the volumes side by side, and examination of fused images. Results: Of 12 enhancing lesions on breast MRI, 7 demonstrated uptake on PET/CT. In the 3 supine-only cases, the fused images were not interpretable because of the marked distortion of the breasts. In the 2 prone cases, the fused images increased our confidence in characterizing a lesion as benign or malignant. Interpretations were confirmed by clinical follow up in 2 or histologic results in 3 patients. Conclusions: PET MRI fusion is feasible and may assist in localizing lesions detected on either study. A more extensive study is underway to confirm the value of this fusion technique.