Histopathology of human coronary atherosclerosis by quantifying its chemical composition with Raman spectroscopy.

BACKGROUND: Lesion composition, rather than size or volume, determines whether an atherosclerotic plaque will progress, regress, or rupture, but current techniques cannot provide precise quantitative information about lesion composition. We have developed a technique to assess the pathological state of human coronary artery samples by quantifying their chemical composition with near-infrared Raman spectroscopy. METHODS AND RESULTS: Coronary artery samples (n=165) obtained from explanted recipient hearts were illuminated with 830-nm infrared light. Raman spectra were collected from the tissue and processed to quantify the relative weights of cholesterol, cholesterol esters, triglycerides and phospholipids, and calcium salts in the examined artery location. The artery locations were then classified by a pathologist and grouped as either nonatherosclerotic tissue, noncalcified plaque, or calcified plaque. Nonatherosclerotic tissue, which included normal artery and intimal fibroplasia, contained an average of approximately 4+/-3% cholesterol, whereas noncalcified plaques had approximately 26+/-10% and calcified plaques approximately 19+/-10% cholesterol in the noncalcified regions. The average relative weight of calcium salts was 1+/-2% in noncalcified plaques and 41+/-21% in calcified plaques. To make this quantitative chemical information clinically useful, we developed a diagnostic algorithm, based on a first set of 97 samples, that demonstrated a strong correlation of the relative weights of cholesterol and calcium salts with histological diagnoses of the same locations. This algorithm was then prospectively tested on a second set of 68 samples. The algorithm correctly classified 64 of these new samples, thus demonstrating the accuracy and robustness of the method. CONCLUSIONS: The pathological state of a given human coronary artery may be assessed by quantifying its chemical composition, which can be done rapidly with Raman spectroscopic techniques. When Raman spectra are obtained clinically via optical fibers, Raman spectroscopy may be useful in monitoring the progression and regression of atherosclerosis, predicting plaque rupture, and selecting proper therapeutic intervention.

Weekly oral etoposide in patients with Kaposi's sarcoma associated with human immunodeficiency virus infection: a phase I multicenter trial of the AIDS Clinical Trials Group.

We conducted a Phase I trial to evaluate the safety, maximally tolerated dose (MTD), antitumor activity, and pharmacology of once-weekly oral etoposide in patients with Kaposi's sarcoma (KS) and AIDS. From September 1990 to October 1991, 27 eligible patients with biopsy-confirmed KS were treated at six etoposide dose levels, ranging from 150 to 400 mg weekly. Patients were treated until their tumor progressed or until unacceptable toxicity developed. On the first day of therapy, etoposide plasma concentrations were measured by high-performance liquid chromatography. The MTD was defined as the etoposide dose that induced reversible grade 3 toxicity in three of six patients during the first 4 weeks. Although dose-limiting toxicity was uncommon during the first 4 weeks of treatment (three of 27 patients), and the MTD was not reached, with longer treatment > 50% of patients developed dose-limiting toxicities, most commonly neutropenia. Responses were observed at all dosage levels (except 350 mg weekly), with partial tumor regression documented in nine (36%) of 25 evaluable patients. There was marked variability in etoposide area under the plasma concentration versus time curve, elimination half-time (t1/2), and urinary excretion. These pharmacokinetic features were not, however, associated with the presence of gastrointestinal symptoms, the severity of side effects, or tumor response. We conclude that weekly oral etoposide can be safely administered to patients with AIDS and KS. The observed antitumor effects over a wide range of doses support further studies with very low and minimally toxic etoposide doses, alone or in combination with other agents.

Lung scan evaluation of thrombolytic therapy for pulmonary embolism.

UNLABELLED: Data from three trials of thrombolytic therapy for pulmonary embolism (PE) were combined to assess the utility of perfusion lung scan defect scoring in predicting the response to thrombolytic therapy. METHODS: Pre- and post-therapy lung scans and duration of symptoms were available for a total of 221 patients, 167 were treated with various thrombolytic regimes and 54 were treated with heparin alone. RESULTS: Improvement in the lung scan defect score was correlated with larger initial defect score (r = 0.53), segmental appearance (r = 0.31) and shorter duration of symptoms (r = 0.20). There was no significant residual correlation between improvement and segmental appearance in a multiple regression analysis after accounting for initial defect score and duration of symptoms. Two lung scan scoring methods (segmental and anterior-posterior method) provided similar results with low interobserver variability (r = 0.90 for both methods). CONCLUSION: This study indicates that the baseline perfusion lung scan defect severity helps to predict the response to thrombolytic therapy.

Two trials of reduced bolus alteplase in the treatment of pulmonary embolism. An overview.

The Bolus Alteplase Pulmonary Embolism (BAPE) Group and a consortium of French investigators utilized essentially the same investigational protocol to test reduced dose bolus alteplase vs full dose 100 mg/2 h alteplase in the treatment of pulmonary embolism (PE). The principal hypothesis was that reduced dose bolus alteplase (n = 96) would result in fewer bleeding complications than full dose 100 mg of 2 h alteplase (n = 44) administered as a continuous infusion to hemodynamically stable patients with PE. To provide data on bolus alteplase's safety profile in a larger sample size than would have been feasible in either trial alone, we present an overview of the BAPE and French trials. There were no differences between the reduced dose bolus and full dose 2 h rt-PA groups with respect to bleeding complications. Therefore, the principal hypothesis of these two randomized controlled trials could not be confirmed. Efficacy was similar in the two treatment groups. Interpretation of the results will vary because the increased convenience and cost savings from using a reduced dose of bolus alteplase may be offset by a higher mortality rate. However, a trial that compared the mortality rates of the two treatment regimens would have required more than 800 patients.

Fundamental dilemmas of the randomized clinical trial process: results of a survey of the 1,737 Eastern Cooperative Oncology Group investigators.

PURPOSE: We studied oncologists' attitudes and behavior with regard to their participation in randomized clinical trials. METHODS: We surveyed the 1,737 physician members of the Eastern Cooperative Oncology Group (ECOG) using the Physician Orientation Profile (POP), a self-administered mailed questionnaire. A response rate of 86% was achieved (1,485 of 1,737); each physician's actual patient accrual was recorded. RESULTS: All respondents indicated that they had a systematic pattern of patient preselection for entry onto trials beyond the formal inclusion/exclusion trial criteria. Eighty-nine percent stated that improving patient quality of life rather than prolonging survival was more personally satisfying. Sixty-two percent did not enter a single patient during the 12-month period following the survey, while 10% entered 80% of all patients during that time. Physicians overestimated their accrual rate by a factor of 6. Eighty-three percent defined randomization and adherence to trial protocol as a serious challenge to their ability to make individualized treatment decisions. CONCLUSION: This study raises questions regarding the following: (1) the perceived generalizability of trial findings, (2) the role of end points other than survival for clinical trials, (3) the consequences of physician overestimation of patient accrual, and (4) the impact of randomized trials on the behavior of clinicians. Further investigation into these critical issues will provide meaningful recommendations to enhance the future design, implementation, and conduct of randomized clinical trials in cancer.

Prognostic significance of right ventricular hypokinesis and perfusion lung scan defects in pulmonary embolism.

We studied the relation between right ventricular (RV) hypokinesis on echocardiography and defects on the initial perfusion lung scan among 90 hemodynamically stable patients with pulmonary embolism (PE). Of the 90, 38 had qualitative evidence of RV hypokinesis, with a mean RV end-diastolic area significantly larger than those with normal RV wall motion (40.0 +/- 10.2 cm2 vs 20.1 +/- 6.4 cm2; p < 0.001). The degree of the perfusion defect was greater in those patients with baseline RV hypokinesis (54% +/- 16% of the lung nonperfused) than in those patients with normal RV wall motion at baseline (30% +/- 18% nonperfused lung; p < 0.001). Receiver operating characteristic curve analysis showed that a perfusion lung scan defect score of 0.3 (i.e., 30% of the lung nonperfused) had a 92% sensitivity for predicting RV hypokinesis and carried a relative risk for observing RV hypokinesis of 6.8 times greater than among those patients with a perfusion scan score of < 0.3. Considering that all patients with recurrent symptomatic PE were in the subgroup with RV hypokinesis (13% vs 0% for those with normal RV wall motion; p = 0.01), a strategy of performing echocardiography in those patients with a perfusion scan defect score of > or = 0.3 appears to identify patients at increased risk for recurrent PE.

Efficacy and safety of repeated boluses of urokinase in the treatment of deep venous thrombosis.

The only Food and Drug Administration-approved thrombolytic regimen for treatment of deep venous thrombosis (DVT) is a 24- to 72-hour continuous infusion of intravenous streptokinase. This approach to DVT thrombolysis is not entirely satisfactory because of the bleeding complications that may accompany this therapy. In the current study, we treated 27 patients with DVT with a novel dosing regimen of urokinase: 1,000,000 U administered as a 10-minute bolus, with a total of 3 boluses given over approximately 24 hours. Patients were given heparin overnight between bolus urokinase doses. Efficacy was assessed by comparing baseline and prehospital discharge vascular imaging studies, which constituted either venous ultrasound or contrast venography. A vascular-imaging panel of physicians, unaware of the sequence of paired studies, found that 14 patients (52%) had clot lysis (6 slight, 6 moderate and 2 marked), 9 (33%) had no change, and 4 (15%) had more extensive thrombosis after treatment (1 slight, 2 moderate and 1 marked). There were no bleeding complications. At 48 hours after starting urokinase, mean plasma fibrinogen levels had decreased 61% from baseline, and the mean bleeding time had increased 28% from baseline (but remained within the normal range). Because of the promising efficacy and safety that were found in this case series, it is concluded that further testing of bolus urokinase is warranted against anticoagulation alone.

Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion.

Data from a non-randomised study have hinted that in patients with acute pulmonary embolism (PE), thrombolysis followed by heparin more rapidly reverses right-ventricular dysfunction and restores pulmonary tissue perfusion than does heparin alone. We have pursued this idea in a randomised protocol. 46 haemodynamically stable patients were randomised to recombinant tissue plasminogen activator (alteplase, rt-PA) 100 mg over 2 h followed by intravenous heparin and 55 to heparin alone. Right-ventricular wall motion was assessed qualitatively, and right-ventricular end diastolic area was estimated by planimetry from echocardiograms at baseline and at 3 and 24 hours. Pulmonary perfusion scans were obtained at baseline and 24 hours. In 39% of rt-PA patients but in only 17% of heparin alone patients right-ventricular wall motion at 24 hours had improved from baseline and in 2% and 17%, respectively, it worsened (p = 0.005). rt-PA patients also had a significant decrease in right-ventricular end-diastolic area during the 24 hours after randomisation and a significant absolute improvement in pulmonary perfusion (14.6% vs 1.5%). No clinical episodes of recurrent PE were noted among rt-PA patients, but there were 2 fatal and 3 non-fatal clinically suspected recurrent PEs within 14 days in patients randomised to heparin alone. rt-PA rapidly improves right-ventricular function and pulmonary perfusion among patients with PE and may lead to a lower rate of adverse clinical outcomes.

Recombinant tissue-type plasminogen activator versus a novel dosing regimen of urokinase in acute pulmonary embolism: a randomized controlled multicenter trial.

Thrombolysis of acute pulmonary embolism can be accomplished more rapidly and safely with 100 mg of recombinant human tissue-type plasminogen activator (rt-PA) (Activase) than with a conventional dose of urokinase (Abbokinase) given as a 4,400-U/kg bolus dose, followed by 4,400 U/kg per h for 24 h. To determine the effects of a more concentrated urokinase dose administered over a shorter time course, this trial enrolled 90 patients with baseline perfusion lung scans and angiographically documented pulmonary embolism. They were randomized to receive either 100 mg/2 h of rt-PA or a novel dosing regimen of urokinase: 3 million U/2 h with the initial 1 million U given as a bolus injection over 10 min. Both drugs were delivered through a peripheral vein. To assess efficacy after initiation of therapy, repeat pulmonary angiograms at 2 h were performed in 87 patients and then graded in a blinded manner by a panel of six investigators. Of the 42 patients allocated to rt-PA therapy, 79% showed angiographic improvement at 2 h, compared with 67% of the 45 patients randomized to urokinase therapy (95% confidence interval for the difference in these proportions [rt-PA minus urokinase] is -6.6% to 30.4%; p = 0.11). The mean change in perfusion lung scans between baseline and 24 h was similar for both treatments. Three patients (two treated with rt-PA and one with urokinase) had an intracranial hemorrhage, which was fatal in one. The results indicate that a 2-h regimen of rt-PA and a new dosing regimen of urokinase exhibit similar efficacy and safety for treatment of acute pulmonary embolism.

Quality-of-life-adjusted survival for comparing cancer treatments. A commentary on TWiST and Q-TWiST.

In chronic disease situations where treatment comparisons favor no particular therapy, or where definitive outcome requires a considerable follow-up period, it is useful to have additional and perhaps intermediate endpoints of relevant clinical significance to compare treatments. One such endpoint is Time Without Symptoms and Toxicity (TWiST) which, together with Q-TWiST, attempts to address the quality of life of patients receiving the competing regimens. This paper provides a commentary on these techniques with an emphasis on the problems inherent in implementing Q-TWiST, a measure that attempts to incorporate patient value preferences into TWiST. It is argued that while Q-TWiST is intuitively appealing in the clinical setting, there are formidable design and psychometric hurdles that must be overcome to fully operationalize the concept.

Characteristics of diet among a culturally diverse group of low-income pregnant women.

This study reports on diet quality and variety in food selection among a culturally diverse group of 335 low-income pregnant Massachusetts women. The Index for Nutritional Quality (INQ), which is the observed nutrient density divided by the recommended nutrient density, was estimated for seven nutrients from data reported on food frequency questionnaires and diet recalls. Mean INQs for protein and vitamin C were above the recommended level of 1.0, whereas INQ for iron was 0.6 or less. Mean INQ for calcium was 1.2 for whites and between 0.9 and 1.0 for non-whites. When comparisons were made among ethnic groups by site of prenatal care, significant differences in INQ were found for all nutrients except iron and vitamin B-6. WIC participants had higher diet quality for protein, calcium, iron, and vitamin B-6 than did non-participants. Employed women had higher protein and zinc INQs than did unemployed women, and non-smokers had higher iron and vitamin B-6 INQs than did smokers. Variety was not significantly correlated with diet quality but differed (p less than .001) among site-specific ethnic groups. We conclude that there is a need for investigation of factors influencing dietary practices that are associated with sites of prenatal care.

Collection efficiency of respirator filters challenged with monodisperse latex aerosols.

Collection efficiency was evaluated for 10 respirator manufacturers' electrostatically-charged dust/mist filters challenged with eight sizes of latex spheres in a range representative of the silica aerosol used in National Institute for Occupational Safety and Health (NIOSH) certification tests. Minimum efficiency occurred at or below the smallest size of 0.102 microns. Appreciable differences were found in the performances of filters distributed by the 10 manufacturers. Filters produced by 1 manufacturer exhibited significantly lower collection efficiency than other filters tested; those produced by 2 manufacturers performed somewhat better than the others tested. Statistical evaluation of Weibull-transformed data using analyses of covariance and Tukey's significant difference test allowed classification of the 10 manufacturers into three performance categories.

Correlates of patient satisfaction with mental health services in a health maintenance organization.

To assess the level and determinants of patient satisfaction with prepaid mental health services, the authors surveyed 124 adult patients who five years earlier had been seen at least once by a mental health professional. Of the 44 percent who returned questionnaires, approximately one third reported satisfaction, one third dissatisfaction, and one third were unsure. Most patients sought help for chronic situational problems and tended to use the services repeatedly over time. Satisfaction was most strongly correlated with the patients' perceptions of their rapport with the provider and slightly less so with their perceptions of the provider's technical competence. Patient characteristics, diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders (DSM 3), and systems issues were of no predictive value. Patients who presented with symptomatic distress not clearly linked to circumstances were likely to be dissatisfied with treatment.

The validity of Pap smear parameters as predictors of endometrial pathology in menopausal women.

Cytopathologists recognize that certain Pap smear findings are suspicious for endometrial pathology in menopausal women. To study their prognostic importance in the directed cervical smear, six parameters were used to evaluate smears for evidence of an endometrial lesion: the presence of (1) histiocytes, (2) multinucleated histiocytes, (3) nonspecific inflammation, (4) bleeding, (5) elevated squamous cell maturation index, and (6) the degree of cytologic atypicality of endometrial glandular cells, expressed as a "score" from 0 to 6. Clinical pathologic correlation of 102 women with these parameters was undertaken. A multivariable statistical analysis determined which of these six parameters was most predictive of an endometrial lesion. Cytologically "scored" endometrial glandular cells was the only parameter predictive of endometrial pathology. Its emergence as the sole prognostic cervical Pap smear parameter for endometrial pathology has not been previously reported. This predictive value was consistent even with control for bleeding history and age. Appropriate interpretation of abnormal Pap smear findings contributes substantial diagnostic information in the evaluation of the endometrium.

Age-specific patterns of diagnosis of acute otitis media.

A retrospective review of clinical experience with the diagnosis of acute otitis media (AOM) in a large pediatric population (age, 0-12 years old) reveals two age-specific patterns of diagnosis: one in preschool children and one in schoolage children. In the population as a whole, AOM is diagnosed most frequently in the first 5 years of life; rates of diagnosis vary with gender (male: female ratio = 1.10) and season (fall/winter peak). In a linear regression model, age, gender, season, and interactions among these account for 52 percent of the variability in diagnostic rates. In children less than 5 years of age, rates of diagnosis vary strikingly with gender and season; the regression model accounts for 55 percent of observed variability in diagnostic rates. In schoolage children (5-11 years old), however, males and females are equally likely to be diagnosed to have AOM, and seasonal variability is blunted; among these children, the regression model predicts only 22 percent of diagnostic rate variability. These findings buttress existing knowledge of the epidemiology of AOM and have important implications for clinical practice, health planning, and pediatric research.

A controlled study of the impact of mental health treatment on medical care utilization.

The authors report on a controlled examination of the effects of mental health intervention on the use of medical services in a health maintenance organization. Thirty-six patients were randomly assigned, after initial evaluation, either to begin immediately short-term (15 weekly session) group therapy or for those same 15 weeks to remain on a waiting list. The results seemed to indicate that both patients treated immediately and patients who were wait-listed reduced their medical utilization. Wait-list patients, however, appeared to reduce health care use more than immediate-treatment patients. Further, examination of the patterns of health care use showed that wait-listed patients were more likely to have changed their patterns of utilization than immediate-treatment patients. These findings, which must be interpreted cautiously because of the small number of subjects, appear to support the results of other studies that indicate that those patients with the least mental health intervention appear to have the greatest reductions in medical utilization.

Heparin inhibits bovine testicular hyaluronidase activity in myocardium of dogs with coronary artery occlusion.

Bovine testicular hyaluronidase (BTH) reduces experimental myocardial infarct size and ameliorates electrocardiographic signs of ischemia. This study was done to determine if heparin, an in vitro inhibitor of hyaluronidase activity, blocks the action of BTH in the myocardium of dogs after coronary artery occlusion. BTH was administered intravenously as 5,000 NF units/kg at 0.5 and 2.5 hours after coronary occlusion. Heparin was administered intravenously as a 150-unit/kg loading dose, followed by 10 units/kg per hour i.v., beginning 15 minutes before coronary occlusion. The area of myocardial ischemia at risk was assessed by a radiolabeled microsphere technique; the area that developed necrosis was assessed by a histochemical technique. In vivo activity of BTH was assessed by a colorimetric analysis of the BTH substrate, i.e., hyaluronic acid (HA), extracted from myocardial tissue. For biochemical analysis of HA, the heart was divided into anterior myocardium, which included ischemic tissue and posterior nonischemic myocardium. The myocardial HA content of dogs treated with BTH plus heparin (anterior, 3.44 +/- 0.40 micrograms HA/mg protein; posterior, 3.69 +/- 0.33 micrograms HA/mg protein) was not significantly different from control (anterior, 3.61 +/- 0.29 micrograms HA/mg protein; posterior, 3.55 +/- 0.23 micrograms HA/mg protein). In contrast, BTH lowered myocardial HA content (anterior, 2.16 +/- 0.21 micrograms HA/mg protein; posterior, 2.08 +/- 0.14 micrograms HA/mg protein) compared with either BTH plus heparin or control groups in both anterior myocardium (p = 0.006) and posterior myocardium (p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

A logistic model based on enzyme activities for the prediction of response of breast cancer patients to chemotherapy.

A logistic regression model, utilizing the activities of certain selected glycolytic enzymes and ER status measured on primary or recurrent lesions, has been applied to predict for response to combination chemotherapy regimens administered to women with advanced breast cancer. The clinical outcome of response or no response was evaluated retrospectively using criteria employed by cooperative group protocols. In 93 cases, 58/61 patients classified as nonresponders and 22/32 patients demonstrating objective responses would have been correctly designated, based on the 50% estimated probability as the level for separation of responders from nonresponders. The overall predictive accuracy of this model was 86%, with apparently greater accuracy for prediction of lack of response. Addition of estrogen receptor status to the model imparted no gain in accuracy of prediction. Application of this model to a prospective study is warranted.

Radiation and nitroimidazoles in supratentorial high grade gliomas: a second clinical trial.

As a continuation of a previous controlled trial using "high-dose" metronidazole as a specific sensitizer of hypoxic cells, we used a more efficient nitroimidazole derivative (misonidazole, MISO) in combination with higher doses of radiation in patients with supratentorial high-grade astrocytomas. Sixty-six patients were stratified according to functional level and histological grading, and randomly allocated within 2 weeks of operation of 1 of 3 therapeutic groups: 1, conventional radiation alone; 2, large fractions of radiation with high-dose metronidazole; and 3, radiation as in Group 2 but with equitoxic doses of MISO. We examined survival as the principal end-point of the study. Neither by increasing the dose of radiation over the previous study, nor by using a more efficient sensitizer, were we able to improve survival over the current conventional daily fractionated radiation.

The lack of relationship between estrogen receptor status and response to chemotherapy.

The possible relationship between estrogen receptors and response of breast cancer patients to chemotherapy was examined in two situations: patients with advanced disease and patients receiving post-surgical adjuvant treatment. In 73 patients with disseminated disease, no relationship between ER status and response to cytotoxic chemotherapy was observed. At this time, 44 of these cases have undergone extramural review; in these 44 cases, we observed no significant relationship between ER status and response to chemotherapy. In a series of 52 patients receiving adjuvant therapy, 27 patients were classified as failures due to recurrence. ER status did not offer prognostic value for failure of patients treated with postsurgical adjuvant therapy. We conclude that the prognostic value of ER data in nonhormonal therapy settings remains to be proven