Joseph J. Sanger

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 Patients were withdrawn from the study when cardiac toxicity developed or the cancer progressed. The mean cumulative dose of doxorubicin tolerated by patients withdrawn from study was 397.2 mg per square meter of body-surface area in the FDC group and 466.3 mg in the FDC + ICRF-187 group (no significant difference).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.

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.

Aortic aneurysm dissection causing V/Q mismatch

A case of unilateral mismatch on a ventilation/perfusion lung scan due to aortic aneurysm dissection is presented. Pulmonary embolism should not be considered the sole cause of unilateral lung mismatch. Clinical evaluation and pulmonary angiography should be used for a definitive diagnosis.

Techniques for multimodality image registration

The authors describe the development of techniques used for cross-modality correlation of medical images. To accomplish this goal, software routines were developed which automate and standardize the comparison of images within and between three-dimensional tomographic imaging modalities. Data from phantoms and clinical studies reflect the success of this technique.<<ETX>>

81mKr gas and 99mTc-MAA V/Q ratio images for detection of V/Q mismatches.

Methods for creating ventilation/perfusion ratio images have been reported previously using radioxenon. With the availability of 81mKr gas, corresponding ventilation and perfusion views in multiple projections to evaluate for V/Q mismatch may be performed more readily. A technique for the creation of a functional V/Q ratio image to highlight V/Q mismatches to aid in the evaluation of pulmonary embolism is described. By removing nonpertinent and distracting information and by converting a ‘cold spot’ imaging modality to a ‘hot spot’ modality, these functional images aid in the synthesis of the information provided by the ventilation and perfusion images. The limitations due to technical artifacts and the advantages of using these functional images are described.

Graphical interface for medical image processing

We have developed a graphical interface which allows users of varying levels of computer experience and proficiency to manipulate medical image-processing data with “point-and-click” ease. The power which had formerly been associated with protocols and shell scripts has been combined with the flexibility and “user-friendliness” of buttons and dialog boxes.

The role of computed tomography in evaluation of skeletal metastases

Computed tomography was performed in 100 patients for additional evaluation of suspected skeletal metastases following radionuclide bone scanning in 86 patients and conventional radiography in all. A retrospective review of these cases revealed that the majority (78%) involved the spine and pelvis. Computed tomography contributed to the diagnosis of a malignancy by revealing a definite destructive lesion of bone in 27 patients who had an abnormal radionuclide bone scan, a normal or inconclusive radiograph, or both. It excluded a malignant lesion in 19 patients. In 38 patients, computed tomography provided additional information that contributed to such aspects of patient care as obtaining tissue diagnosis, determining the extent of lesions, and evaluating the response to treatment. False diagnoses were made in two patients. Detection by computed tomography of a skeletal lesion and histologic documentation, frequently by computed tomography-guided percutaneous needle aspiration biopsy, greatly curtailed an otherwise extensive search for the primary site. Furthermore, this information altered the treatment plan by obviating the need for radical resection or biopsy of the primary tumor and by directing the choice of an appropriate chemotherapeutic regimen.

Breakdancer's pulmonary embolism

A case of pulmonary embolism caused by breakdancing is reported. There was no clinical suspicion of pulmonary embolism.