Cardiotoxicity in patients receiving transtuzumab (Herceptin): primary toxicity, synergistic or sequential stress, or surveillance artifact?

Human epidermal growth factor receptor-2 (HER2) is a member of the epidermal growth factor receptor family, which produces factors that are considered to be important mediators of cell growth. Overexpression of HER2, which occurs in approximately 25% to 30% of human breast cancers, has fostered considerable interest in innovative therapeutic modalities designed to target tumor cells demonstrating such overexpression. Trastuzumab (Herceptin; Genentech, San Francisco, CA), a humanized monoclonal antibody developed to target the HER2 receptor, is the most widely studied example of such a modality. In early clinical studies with trastuzumab, cardiomyopathy was observed with a clinical expression similar to that seen with the anthracyclines (ie, a potentially progressive decrease in cardiac systolic function). A number of possible explanations for this cardiotoxicity are explored in this report. The first is that trastuzumab has inherent toxicity. This consideration has some theoretical interest, since fetal myocardial cells exhibit HER2 receptors and the adult myocardium expresses HER3 receptors. A second possibility is that sequential stresses following doxorubicin administration contribute to cardiac dysfunction. A third explanation is that observational artifacts lead to an overestimation of trastuzumab cardiotoxicity. Approaches for additional study of the extent and severity of trastuzumab cardiotoxicity are briefly addressed.

Long-term results and pharmacokinetics of high-dose paclitaxel in patients with refractory epithelial ovarian carcinoma.

The purpose of this study was to analyze the efficacy and toxicity of a high dose of paclitaxel in patients with ovarian cancer refractory to platinum chemotherapy. Another phase II study of hydroxyurea was run in the same patient population. Fifty patients with measurable ovarian cancer were entered on this phase II study at The University of Texas M. D. Anderson Cancer Center. Treatment consisted of 250 mg/m2 of paclitaxel given by continuous intravenous infusion over 24 h every 3 weeks. Patients with disease unresponsive to paclitaxel could then be crossed over to hydroxyurea, and vice versa. Twenty-five (53%) out of 47 evaluable patients had a response (two complete responses and 23 partial responses). Twelve (26%) patients had stable disease. The median survival was 11.3 months. The main toxic effect was neutropenia (98% of patients) with 28 (9%) episodes of neutropenic fever. Neutropenia required therapy with granulocyte colony-stimulating factor. Other side effects were alopecia (100%), anemia (98%), gastrointestinal problems (57%), stomatitis (27%), and neurotoxicity (55%). Paclitaxel administered at a high dose as a single agent proved to be very active in patients who had platinum-refractory ovarian cancer and was well tolerated. Further studies of high-dose paclitaxel in patients with ovarian carcinoma are indicated.

Quantitative coronary arteriography and its assessment of atherosclerosis. Part I. Examining the independent variables.

BACKGROUND: Previous work has demonstrated that quantitative coronary arteriography (QCA) can accurately measure phantom images to within +/- 0.1 mm and has been accepted as a reliable and reproducible method of measuring human coronary artery disease (CAD). Assessment of CAD by QCA involves the measurement of numerous variables, which are currently required to calculate stenosis flow reserve (SFR). METHODS AND RESULTS: In this study 1040 stenotic lesions were analyzed by two well-accepted methods with demonstrated accuracy and reproducibility. These methods measure percent diameter stenosis (%DS), absolute diameter, percent area stenosis, length, as well as entry and exit angles to and from a stenotic coronary artery lesion respectively. Based upon these results, the mean +/- standard deviations and range seen in CAD were determined for each of these independent variables. This study demonstrated that atherosclerotic coronary artery lesions do not appear to exceed an entry angle of -39 degrees, and exit angle of +35 degrees, or an absolute length of 4.84 cm when accurately measured by QCA. It was also noted that, once percent diameter stenosis exceeded 89% (regardless of the visual estimate) or percent area stenosis exceeds 99%, coronary arteries become completely occluded as measured by QCA. CONCLUSIONS: While previously suspected that once certain critical limits are exceeded in the deposit of cholesterol and calcium within the coronary artery, the artery will close, this study demonstrated by QCA what the limitations in human coronary arteries appear to be. These limits may be in part due to turbulent factors resulting in platelet activation or local mediators from endothelium of the coronary artery.

Late doxorubicin-associated cardiotoxicity in children. The possible role of intercurrent viral infection.

BACKGROUND: The most frequently encountered doxorubicin related cardiac toxicity is a dose-related myocardial dysfunction occurring 1-6 months after chemotherapy. Recently, late cardiotoxicity has been the focus of interest. This paper explores the possibility that acute intercurrent viral illness may trigger late cardiotoxicity. METHODS: Thirty selected pediatric patients were followed for changes in their echocardiographically measured fractional shortening (FS) for 2-10 years after completion of their doxorubicin chemotherapy. They were divided according to the dose of doxorubicin they received (< 300 mg/m2 or > or = 300 mg/m2) and to whether the manifestations of an acute intercurrent viral illness during the observation period were documented. Eleven patients experienced such infections. RESULTS: Changes in FS demonstrated two different responses. The usual response to doxorubicin was a gradual, dose-related fall in FS, followed by recovery; while the second response included an unexpected, late, sudden decrease in FS. Four patients in the low dose subgroup experienced an acute intercurrent viral illness, but none of these demonstrated the unexpected decrease. Of the seven patients who acquired such illness in the high dose subgroup, five demonstrated the sudden, late decrease in FS, with two of them developing severe, reversible congestive heart failure. CONCLUSIONS: The most likely explanation for the late, sudden decrease in FS is an additional stress in patients who already have sustained subclinical cardiac damage as a result of their doxorubicin chemotherapy. An acute intercurrent viral illness may have triggered late cardiac dysfunction in some of these patients.

Cardiac diastolic function in pediatric patients receiving doxorubicin.

The purpose of the study was to compare systolic and diastolic function in pediatric patients treated with doxorubicin. Left ventricular function was evaluated in 61 children prior to and following chemotherapy. None had clinical evidence of cardiac decompensation prior to treatment. All received relatively low cumulative doses of doxorubicin; the majority received the drug by continuous infusion. Systolic function was estimated using fractional shortening; diastolic function was estimated using A wave velocity, E wave velocity, E to A ratio, and deceleration time. There was a small but significant decline in systolic cardiac function as estimated from changes in fractional shortening that could not be appreciated in any of the measured parameters of diastolic function. A variety of reasons that could be responsible for the absence of significant changes in diastolic function are discussed. For the present, estimations of systolic function are preferred over the studied parameters of diastolic function in the evaluation of cardiac status in pediatric patients receiving doxorubicin containing regimens.

The M. D. Anderson Cancer Center experience with Taxol in metastatic breast cancer.

Taxol was evaluated in metastatic breast cancer in three trials. In the first, a phase II study, 25 patients who had received only one prior regimen of chemotherapy received Taxol (starting dose of 250 mg/m2). The response rates were 12% complete, 44% partial, and 32% minor. The median duration of response was 9 months (range, 3 to 19 months). The median survival was 20 months (range, 5 to 29+ months). Toxic effects were granulocytopenia less than 500/mm3 in 85% of all courses but serious infection in only 6% of courses, myalgias, and cumulative neuropathy. The second trial was a phase I study of Taxol by 24-hour infusion sequenced with doxorubicin by 48-hour infusion as initial chemotherapy for metastatic disease. In arm 1, Taxol preceded doxorubicin. The starting doses were 125 mg/m2 Taxol, 60 mg/m2 doxorubicin. Neupogen (5 micrograms/kg) was given subcutaneously on days 5 through 19. Ten patients received 96 courses. The maximum tolerated dose was defined by mucositis and infection at the starting dose. Cumulative thrombocytopenia occurred in subsequent courses. The unexpectedly severe toxic effects at doses that were low by comparison to other studies suggested schedule-related toxicity. Therefore, in arm 2 the sequence has been reversed: doxorubicin precedes Taxol. Doses have been escalated to 180 mg/m2 Taxol with 60 mg/m2 doxorubicin without dose-limiting toxic effects occurring. The third trial, a phase II study in patients who have received three or more prior chemotherapy regimens, is ongoing. Twenty-one of a planned 35 patients have been entered. Taxol has shown significant antitumor activity in minimally pretreated patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac emergencies in the cancer patient.

Cardiac emergencies may be encountered during the management of patients with cancer, both in those with underlying cardiovascular disease and those with no previous history of cardiac problems. Both surgical and medical cancer treatment modalities may exacerbate preexisting cardiac conditions. Some antineoplastic agents can adversely affect the coronary arteries, myocardium, or pericardium. It has also been recognized that cardiac damage due to radiotherapy and chemotherapy may become clinically significant many years after therapy has been completed. Treatment of urgent cardiac problems in the cancer patient may differ from that recommended for other patient groups, since many cancer patients are not ideal candidates for some of the newer cardiac agents. Management of these conditions must therefore be tailored to the individual patient.

Nodus migrans: the case of the migrating knot.

Flow-directed pulmonary artery catheters provide important information regarding intravascular volume status, cardiac function and vascular resistance. We describe an unusual complication of pulmonary artery catheterization in which a knot formed at the distal end was torn away from the catheter body and migrated from its original position in the right subclavian vein to a distal branch of the right pulmonary artery. Careful attention to insertion and withdrawal techniques could prevent this potentially serious complication.

Postoperative atrial fibrillation in cancer surgery: preoperative risks and clinical outcome.

Postoperative atrial fibrillation (AF) is a recognized complication of cancer surgery. The purpose of this study was to define preoperative risk factors for AF, and to evaluate the clinical significance of the arrhythmia. We reviewed the medical records of 43 patients with postoperative AF admitted to the surgical intensive care unit (SICU). All patients were older than 60 years, 79% had a history of cigarette smoking, and 44% had hypertension. AF occurred an average of 2.8 days following surgery, and lasted an average of 2.1 days. No significant complications developed, and there were no long-term sequelae. This study suggests that, in cancer patients, postoperative AF is a disease of elderly patients. In addition the arrhythmia appears to be a relatively transient and benign phenomenon. Prolonged monitoring in an intensive care setting may not be necessary for asymptomatic, hemodynamically stable patients.

Using quantitative coronary arteriography to redefine SPECT sensitivity and specificity.

Previous studies looking at the sensitivity, specificity, and predictive accuracy of single photon emission computed tomography (SPECT) have been based upon the results obtained by visual interpretation of coronary arteriograms. Since the results of visual and quantitative determination of percent diameter stenosis have been shown to be statistically different, the results obtained from SPECT imaging when compared to quantitative methods for assessing coronary artery disease would be expected to provide a more correct assessment of sensitivity, specificity, and predictive accuracy. To determine the "true" sensitivity, specificity, and predictive accuracy of SPECT in diagnosing coronary artery disease, this study compared the results obtained in 44 SPECT images (20 thallium and 24 teboroxime) with the results obtained when quantitative coronary arteriography was used to analyze the coronary arteriograms. These 44 cases were then compared against 8 different definitions of significant coronary artery disease, varying from 30 to 80%, to yield 352 comparisons. The maximum specificity and predictive accuracy was found when 45% diameter stenosis was used to define the presence or absence of significant disease. At 45% diameter stenosis, SPECT imaging demonstrated an 86% sensitivity, 78% specificity, and 94% predictive accuracy with only 6% false positives. In 100% of the cases where 45% diameter stenosis was used to define the presence of disease and exercise failed to demonstrate ST segment changes or angina, when SPECT imaging demonstrated a perfusion defect(s), quantitative coronary arteriography agreed with SPECT imaging results.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial infarction due to intracoronary thrombi without significant coronary artery disease in systemic lupus erythematosus.

Acute myocardial infarction is a potentially fatal complication of SLE. Reported mechanisms include atherosclerosis, arteritis and coronary arterial spasm. The following case report presents a fourth possible cause; intracoronary thrombus with angiographically normal coronary arteries in a patient with active lupus and AMI.

Endocarditis caused by beta-lactamase-producing Haemophilus influenzae.

We have described a case of tricuspid valve endocarditis caused by beta-lactamase-producing H influenzae that responded well to four weeks of cefamandole therapy.

Infective endocarditis of a bicuspid aortic valve caused by Hansenula anomala.

Infective endocarditis due to Hansenula anomala developed on a bicuspid aortic valve in a 40-year-old man. H. anomala, an ascomycetous yeast, may be a member of the normal flora of the throat and alimentary tract in humans but has not been previously known to be pathogenic in humans. A past history of intravenous drug use may have contributed to the development of disease in this patient.

Pure vasodepressor carotid sinus hypersensitivity. Unusual cause of recurrent syncope.

Recurrent syncope in a 53-year-old man was found to be due to vasodepressor carotid sinus hypersensitivity. Establishment of the diagnosis required monitoring of both the electrocardiographic changes and the blood pressure during carotid sinus massage. Current therapeutic approaches to patients with symptomatic vasodepressor hypersensitivity are discussed.

Isolated tricuspid valve prolapse diagnosed by echocardiography.

Isolated tricuspid valve prolapse in the absence of mitral valve prolapse or other cardiac defects has not been previously noted. This report describes a patient who on both M-mode and two-dimensional echocardiography demonstrated tricuspid prolapse without other associated abnormalities. The implications of this finding are discussed.