William I. Ganz

Review of tests for monitoring doxorubicin-induced cardiomyopathy.

The objective of this review is to make physicians aware of new radionuclide methods to detect cardiac effects of chemotherapeutic drugs. This knowledge is important because of the limitations of the physical examination and the electrocardiogram for detecting early reversible cardiac damage. Presently left ventricular ejection fraction (LVEF) is routinely used to screen for cardiotoxicity. Since LVEF obtained by radionuclide angiocardiography is more accurate than the LVEF estimated by echocardiography, serial radionuclide LVEF monitoring is most commonly used to monitor cardiotoxicity. Diastolic measurements of left ventricular function (such as peak filling rate) are now being added to routine LVEF measurements to enhance standard radionuclide evaluation. This screening test should be done prior to beginning therapy and at appropriate points based on the baseline study, therapy scheme and the patients clinical status. At some centers, exercise LVEF methods are being used to determine if cardiac reserve is adequate for the patient to tolerate additional chemotherapy when cardiac injury may be present. Previously, endomyocardial biopsy was needed to detect and confirm early anthracycline cardiotoxicity. This invasive test may be replaced by a new noninvasive in vivo method using radioactive monoclonal antibodies against cardiac muscle (indium-111-antimyosin). Because cardiac failure has been associated with adrenergic neuron injury, it has been proposed that radioactive methyliodobenzylguanine may detect the adrenergic abnormality which may predict future development of congestive heart failure or sudden death months after therapy is discontinued. Advantages and disadvantages of these methods in evaluating cardiotoxicity, and an algorithm to optimally monitor antitumor therapy-induced cardiomyopathy are discussed.

99mTc-HMPAO SPECT of the brain in mild to moderate traumatic brain injury patients: Compared with CT—a prospective study

Single photon emission computed tomography (SPECT) with Technetium-99m hexamethyl propylenamine oxime (Tc-99m-HMPAO) was used in 20 patients with mild to moderate traumatic brain injury (TBI) to evaluate the effects of brain trauma on regional cerebral blood flow (rCBF). SPECT scan was compared with CT scan in 16 patients. SPECT showed intraparenchymal differences in rCBF more often than lesions diagnosed with CT scans (87.5% vs. 37.5%). In five of six patients with lesions in both modalities, the area of involvement was relatively larger on SPECT scans than on CT scans. Contrecoup changes were seen in five patients on SPECT alone, two patients with CT alone and one patient had contrecoup lesions on CT and SPECT. Of the eight patients (50%) with skull fractures, seven (43.7%) had rCBF findings on SPECT scan and five (31.3%) demonstrated decrease in rCBF in brain underlying the fracture. All these patients with fractures had normal brain on CT scans. Conversely, extra-axial lesions and fractures evident on CT did not visualize on SPECT, but SPECT demonstrated associated changes in rCBF. Although there is still lack of clinical and pathological correlation, SPECT appears to be a promising method for a more sensitive evaluation of axial lesions in patients with mild to moderate TBI.

Detection of early anthracycline cardiotoxicity by monitoring the peak filling rate.

Three patients developed clinical congestive heart failure after cumulative doxorubicin doses of 264, 440, and 450 mg/m2, respectively, despite serial monitoring of systolic cardiac function by resting gated radionuclide scanning. All three patients had depressed diastolic function, as shown by a decreased peak filling rate preceding a change in systolic function, which was assessed by left ventricular ejection fraction prior to the development of clinical congestive heart failure. We recommend serial monitoring of the peak filling rate, in addition to left ventricular ejection fraction. If broader experience confirms our impression that the peak filling rate is more sensitive than the current standard assessment of left ventricular ejection fraction, new guidelines may need to be drawn to monitor cardiotoxicity of anthracyclines and anthraquinones.

Atypical osteomyelitis of the skull base.

Most cases of osteomyelitis of the skull base occur as a result of inadequately treated localized malignant otitis externa. We present four patients with osteomyelitis of the skull base who did not present initially as malignant otitis externa. Increased morbidity may occur when these atypical cases are not promptly recognized and treated.

Technetium-99m-labeled platelets: Comparison of labeling with a new lipid-soluble Sn(II)-mercaptopyridine-N-oxide and 99mTc-HMPAO

Platelets pretinned with a neutral Sn(II)-2-mercaptopyridine-N-oxide (SN-MPO) were labeled with 99mTc and compared to those labeled with 99mTc-HMPAO. The conditions of labeling platelets, e.g. concentrations of platelets and Sn(II)-MPO, 99mTc in ACD-saline or ACD-plasma media, pH and incubation time, were optimized using canine platelets. Moderate labeling efficiency was obtained with 20 micrograms of tin(II) chloride and 30 min incubation with Sn-MPO and pertechnetate. The viability of labeled platelets was determined by platelet recovery and platelet survival times in Beagle dogs. The labeling efficiency with platelets from 43 mL of blood was 62.8 +/- 7.6%. The platelet recovery was 35.7 +/- 5.0% and exponential survival time was 34.6 +/- 3.1 h compared to 43.3 +2- 12.0% and 29.5 +/- 3.3 h for 99mTc-HMPAO-labeled platelets. These values were significantly (P less than 0.01) lower than 111In-labeled platelets. Biodistribution in dogs indicates lower retention in blood, spleen and liver after some initial 99mTc excretion in urine. The platelet deposition with 99mTc platelets (Sn-MPO method) on polyurethane angio-catheters was similar to 99mTc-HMPAO-labeled platelets. This study indicates that the platelets could be successfully labeled with pertechnetate in a cost-effective manner for the evaluation of thromboembolic complications.

The Fate of Emboli Post-Recanalization of Thrombus-Occluded Artery and Vein in Yorkshire Pigs

Aged thrombi (4-day old) could neither be disaggregated by thrombolytic enzymes nor removed by balloon thrombectomy. Metabolic fate of thrombi post-recanalization was determined with 111In labeled platelets. Aged (4-day) labeled platelet-emboli were induced in the femoral, carotid artery and jugular vein in twelve Yorkshire pigs. The thrombi were pulverized with a high speed impeller (80,000 RPM) and the debri generated were flushed with the effluent with heparinized saline and allowed to localize in the down-stream perfusion beds of lungs, liver, legs or brain. The debri generated during recanalization of occluded vessels were also analysed for size distribution by differential filtration (5, 12, 75, 500 and 1000 μm) and radioactivity was determined with a Geiger probe. Autologous platelets were labeled with lllln tropolone (400-500 μCi); 111In labeled platelet-thrombi were induced.by thrombin addition in segments (4-5 cm of ligated vessels in femoral/carotid artery and jugular vein. The residual thrombi were monitored with a Geiger probe and gamma counter. The emboli in the leg-muscle, lungs and brain were imaged with a gamma camera and quantified with an ionization chamber. Filtration indicated the average size of emboli (75 μm). Most of debri from the jugular vein were found in the lungs and liver. Small amount of debri from carotid and femoral artery was found in brain and leg muscle respectively. Labeled platelets provided a simple technique for determination of the fate of emboli generated by recanalization in the pig model.