RATIONALE AND OBJECTIVES:Bringing a new imaging technology to market is a complex process. Beyond conceptualization and proof of concept, obtaining U.S. Food and Drug Administration (FDA) approval for clinical use depends on the documented experimental establishment of safety and efficacy. In turn, safety and efficacy are evaluated in the context of the intended use of the technology. The purpose of this study was to examine a conceptual framework for technology development and evaluation, focusing on new breast imaging technologies as a highly visible and current case in point. MATERIALS AND METHODS:The FDA views technology development in terms of a preclinical and four clinical phases of assessment. With a concept of research and development as a learning model, this phased-assessment concept of regulatory review against intended use was integrated with a five-level version of a hierarchy-of-efficacy framework for evaluating imaging technologies. Study design and analysis issues are presented in this context, as are approaches to supporting expanded clinical indications and new intended uses after a new technology is marketed. CONCLUSION:Breast imaging technologies may be intended for use as replacements for standard-of-care technologies, as adjuncts, or as complementary technologies. Study designs must be appropriate to establish claims of superiority or equivalence to the standard for the intended use. Screening technologies are ultimately judged on their demonstrated effectiveness in decreasing cause-specific mortality through early detection, but they may be brought to market for other uses on the basis of lesser standards of efficacy (eg, sensitivity, specificity, positive and negative predictive value, and stage of disease detected).

A 10-year-old girl with uncorrected tetralogy of Fallot with pulmonary atresia presented with fevers of unknown origin and left lung infiltrates. At autopsy, necrotizing vascular changes resembling those of severe pulmonary hypertension (grade VI in the Heath-Edwards classification) were confined to the left lung. Pulmonary blood flow and pressure were greater in the left lung and were provided by an enlarged collateral artery arising directly from the descending thoracic aorta. To our knowledge, this is the first report of necrotizing arteritis of the pulmonary arteries in uncorrected tetralogy of Fallot with pulmonary atresia.

To determine if serial sectioning and multiple level evaluation increase the sensitivity of endomyocardial biopsy for the detection of myocarditis, we prospectively studied all diagnostic endomyocardial biopsies between 1986 and 1989. Biopsies were embedded in paraffin, serially sectioned, and every 4-mu-m section was mounted in ribbons on glass slides. Every fifth slide was stained with hematoxylin and eosin and examined for myocarditis by the Dallas criteria (myocyte necrosis and inflammatory cells). Of a total of 153 biopsies, 20 cases (13%) were diagnostic of myocarditis on at least one section. Four biopsies (25%) were positive at slide Level 1, and 15 (75%) by slide Level 5; in five cases (25%), diagnostic foci were present only at or after slide Level 10. Multiple levels should be performed in the histologic evaluation of endomyocardial biopsies to increase the sensitivity of endomyocardial biopsy in the evaluation of myocarditis.

A case of arterial dissection of the right coronary artery secondary to angioplasty guidewire manipulation is presented. No balloon inflation was performed. The histologic appearance of the involved arterial segment was similar to that found in the left anterior descending coronary artery, which had undergone successful balloon dilatation. Both arteries demonstrated medial disruption and fibrointimal proliferation. The pathologic features of angioplasty-induced vascular injury may occur with or without balloon inflation.

A comparative morphologic study of aortic changes with aging was conducted in different populations in an attempt to separate the effects of hypertension and atherosclerosis. Chinese and the occidental populations were chosen, as they are known to have a high prevalence of hypertension and atherosclerosis, respectively. Aortic tissue was collected from occidental (American and Australian) and Chinese populations from three geographic locations. Postmortem specimens were obtained from four fixed locations: ascending aorta (A), descending thoracic aorta (B), and abdominal aorta (suprarenal [C] and above the aortic bifurcation [D]). Histologic sections were used to measure aortic circumference, medial thickness, intimal thickness, and grade of atherosclerosis. Kidney sections were used to confirm the presence or absence of hypertension. A total of 302 cases (age range, 19 to 104 years; Male-to-female ration, 2:1) were studied: 112 Americans, 80 Australians, and 110 Chinese. Cases were divided into three age groups: 19 to 44; 45 to 64; and 65 years and older. The aortic circumference progressively decreased from sites A to D in all populations and age groups. The aortic circumference increased with age, and the increase was independent of the aortic location. When the populations were separated, however, the greater increase was at location A in the Chinese (P = .008) and locations D in the occidental (P = .13), a population contrast that was significant only in location A. Intimal thickness increased with advancing age and was maximal in the abdominal aorta. The population differences also were significant for intimal thickness and were significantly greater in the occidental population in B, C, and D locations, whereas for atherosclerosis significance was only seen in location D. Hypertension (as defined by the morphologic changes in the kidney) after adjusting for age, height, and weight resulted in no statistical significant effect on aortic circumference or on intimal thickness, but did show a significant increase in atherosclerosis score at locations B, C, and D. Also after adjusting for age, height, and weight, the Chinese had a significantly larger aortic circumference in location A compared with the occidental population, whereas in location D the occidentals with hypertension had a significantly larger circumference compared with Chinese, probably due to an interaction of atherosclerosis and hypertension. After similar adjustments, the medial thickness in locations A and C, the intimal thickness in B, C, and D, and atherosclerosis score in D were significantly greater in occidental than Chinese populations.(ABSTRACT TRUNCATED AT 400 WORDS)

Eosinophils have been associated with endomyocardial fibrosis. However, their effect on the myocardium and the reactions they elicit have not been emphasized. We describe four patients with extensive myocardial eosinophilic infiltration with and without endomyocardial fibrosis. Patients with a short duration of disease had eosinophilic infiltrates, myocardial eosinophilic abscesses containing granular eosinophilic material, and/or Charcot-Leyden crystals with and without profuse histiocytic and giant cell reaction with granuloma formation. In the early phase, the granular eosinophilic material can be visualized by the Luna stain and/or by electron microscopic examination. In patients with a long duration of symptoms, well-developed granulomas and profuse fibrosis are seen and eosinophilic material may not be visualized. Toxic eosinophil granular protein may be involved in the development of these lesions.

Fifty-two patients with recently diagnosed idiopathic dilated cardiomyopathy were studied to determine the incidence of myocarditis; patients were randomly assigned to receive either conventional therapy alone or conventional therapy plus prednisone to assess possible therapeutic efficacy with regard to survival. Inflammatory criteria were present in 23% of the population studied with 13% having overt myocarditis according to the Dallas criteria. The addition of prednisone to conventional therapy did not improve survival in a homogeneous population with new-onset dilated cardiomyopathy. Furthermore, the diagnosis of myocarditis by endomyocardial biopsy did not influence 2-year survival once dilated cardiomyopathy had developed. Biopsy-documented myocarditis resolved in all patients, according to results of 3-month follow-up endomyocardial biopsies, regardless of treatment group. There was a trend for patients with a left ventricular ejection fraction less than 20% to show reduced survival at 2 years compared to the group with a higher ejection fraction (p = 0.07). Right ventricular dysfunction determined at catheterization was present in 20 of 52 patients and was the most significant predictor of survival. Patients with precerved right ventricular function had a 95% 24-month survival rate compared to 47% for patients with right ventricular diastolic dysfunction (right ventricular end-diastolic pressure ≥11 mm Hg) (p = 0.005).

Acute in vitro histologic studies have shown that the pulsed xenon chloride excimer laser causes precise microablation without the surrounding thermal tissue injury associated with frequently used continuous-wave lasers such as the argon, carbon dioxide, and neodymium:yttrium aluminum garnet lasers. However, the in vivo healing response of artery wall to excimer laser injury is not known. Accordingly, a xenon chloride excimer laser (308 nm, 40 nsec pulse width, 39 mJ/mm2/pulse) was transmitted via a 600 micron fused silica fiber to create 420 craters of varying depths (30 to 270 micron) in 21 normal canine femoral and carotid arteries. At 2 hours, 2 days, 10 days, and 42 days after excimer laser ablation, the artery segments were perfusion fixed in situ and analyzed by light, scanning, and transmission electron microscopy. At 2 hours, craters were covered by a carpet of platelets and entrapped red blood cells. Fibrin and exposed collagen fibers were seen at the crater base. There was a sharp demarcation of the crater-artery wall interface without lateral laser tissue injury. At 2 days, adherent platelets persisted with thrombus covering the base of the craters. Early healing responses were present, consisting of polymorphonucleated leukocytes and new endothelial cells, which extended over the crater rims. At 10 days, no thrombi were seen, and healing continued with almost complete reendothelialization. Macrophages, fibroblasts, fibrin, and entrapped red blood cells were present below the reendothelialized surface. At 42 days, healing was complete with obliteration of the craters by fibrointimal ingrowth. The surface was completely covered by a smooth monolayer of axially aligned endothelial cells. There were no aneurysms or surface hyperplastic responses. These favorable healing responses in normal canine arteries suggest that pulsed lasers with high tissue absorption coefficients, such as the xenon chloride excimer laser, may be suitable energy sources for clinical laser angioplasty procedures. However, further studies in atherosclerotic animals are required before human clinical responses can be accurately predicted.

Ventricular/vascular coupling dynamics and regional hemodynamics of five hypertensive baboons with concentric left ventricular (LV) hypertrophy (mean arterial pressure +/- SD, 148 +/- 16 mm Hg; LV mass/body weight ratio 3.42 +/- 0.8) were compared with five normotensive controls (mean arterial pressure 89 +/- 3 mm Hg; LV mass/body wt ratio 2.73 +/- 0.5) at different mean arterial pressures. Ventricular/vascular dynamics were assessed by aortic input impedance, pulsatile/total power ratio, effective arterial elastance and compliance from a three-element Windkessel "lumped" model of the circulation. Regional arterial dynamics were assessed by pulse-wave velocities and local reflection coefficients. Systemic arterial compliance was similarly decreased with elevated pressure in both groups but was significantly more reduced for the hypertensive group compared with control animals at control (0.49 +/- 0.16 vs. 0.96 +/- 0.09 ml/mm Hg; p less than 0.05) and acutely lowered arterial pressure (0.62 +/- 0.26 vs. 1.41 +/- 0.24 ml/mm Hg, respectively). Changes in compliance were paralleled by differences in effective arterial elastance derived from cineventriculographic pressure-volume ratios. Regional foot-foot and apparent phase pulse-wave velocities were significantly increased for distal aortic segments of the hypertensive animals during elevated pressures compared with controls (cff, 17.5 +/- 7.5 vs. 8.7 +/- 3.0 m/sec; p less than 0.05). Histology of the aorta revealed significant increases in collagen content (microgram/mg dry wt) from proximal to distal aortic segments (27 +/- 2 vs. 38 +/- 6; p less than 0.005) in hypertensive animals but not in controls (27 +/- 2 vs. 32 +/- 6; NS). With pharmacological normalization of systemic arterial pressures, hypertensive baboons developed aortic wave speeds similar to controls but manifested significantly reduced compliance compared with controls. In contrast, with acute elevations of pressure, systemic arterial aortic compliances were similar for both groups, but distal pulse-wave velocities were significantly increased for hypertensive animals compared with controls. We conclude that measures of ventricular/vascular coupling and arterial dynamics are determined by both the level of arterial pressure and the physical characteristics of the cardiovascular system in chronic systemic hypertension and pressure overload ventricular hypertrophy.

The prevalence of myocarditis was retrospectively evaluated in 71 consecutive necropsy patients who died from acquired immunodeficiency syndrome (AIDS) between 1982 and 1986. Myocarditis was found in 37 cases (52%). Biventricular dilation at necropsy was present in seven cases (10%) and was accompanied by myocarditis in each case; fatal congestive heart failure occurred in four of these seven cases. Although viral, protozoan, bacterial, fungal and mycobacterial opportunistic pathogens were present in myocardial sections of 7 of 37 myocarditis cases, the etiology of myocarditis in the majority of these patients with AIDS remained idiopathic. Thus, myocarditis is a frequent finding at necropsy in patients with AIDS and may contribute to the development of biventricular dilation.

From September 1983 through November 1986, autopsies were performed on 6810 patients at the Office of the Maryland Medical Examiners; of these 40 had detectable cocaine, its metabolites, or both in body fluids. These patients were divided into two groups: natural cocaine-associated deaths (31 patients, mean age 28 +/- 5 years, blood level of cocaine 5.3 +/- 8.1 mg/L) and homicide deaths with detectable cocaine (nine patients, mean age 33 +/- 8 years, blood level of cocaine 0.3 +/- 0.3 mg/L). Cocaine-associated deaths were compared to a control group of 27 victims of sudden traumatic death (mean age 34 +/- 5 years). Total thrombotic occlusion of the left anterior descending coronary artery overlying mild coronary atherosclerosis occurred in one patient with cocaine-associated death. Results of histologic examination showed myocarditis (mononuclear infiltrate) in 8 of 40 (20%) patients dying with detectable cocaine in body fluids compared to 1 of 27 victims of sudden traumatic death (3.7%, p less than or equal to 0.05). Contraction band necrosis occurred in 25% of cocaine-associated deaths compared to a 41% incidence among victims of sudden traumatic death. We conclude that myocarditis occurs frequently in patients dying of cocaine abuse and may represent microvascular injury.