Dr. Awadhesh Kr. Sharma

Peroxisome Proliferator Activated Receptor Gama Agonists : Their Role as Vasoprotective Agents in Diabetes

Florian Blaschke, MD, Evren MD, Willa A, MD

Airway smooth muscle as a Target for Asthma therapy

Julian Solway, M.D. and Charles G. Irvin, Ph.D.

The evolving role of MRI in the detection and evaluation of breast cancer

Robert A, Smith Ph.D.

Peroxisome Proliferator Activated Receptor Gama Agonists : Their Role as Vasoprotective

Agents in Diabetes

Florian Blaschke, MD, Evren MD, Willa A, MDDepartment of Endocrinology, University of California

The incidence of type 2 diabetes is increasing dramatically in

Western industrialized societies because of increasing obesity,

sedentary lifestyles and an aging population. Diabetes mellitus is

associated with an increased risk of developing atherosclerotic

vascular disorders (including coronary, cerebrovascular, and

peripheral artery disease) and cardiovascular disease accounts for

upto 80% of premature excess mortality in diabetic patients.

Consequently, both type 1 and type 2 diabetes are considered a

coronary artery disease (CAD) risk equivalent.

Metabolic syndrome, a constellation of metabolic alterations

associated with obesity, sedentary lifestyle, and ethnic

background, is a major risk factor for subsequent development of

type 2 diabetes and CAD, and is defined by the National

Cholesterol Education Program Adult Treatment Panel III as three

or more of the following five conditions:

Fasting hyperglycemia ( 110 mg/dl)

Hypertension (130/85 mmHg)

Hypertriglyceridemia ( 150 mg/dl)

Reduced high density lipoprotein (HDL : men< 40 mg/dl, women

< 50 mg/dl)

Increased waist circumference (men > 102 cm : women > 88 cm)

Insulin resistance, defined as a defect in the ability of insulin to

derive glucose into its major target tissue, skeletal muscle, is

usually a component of the metabolic syndrome. It is key factor in

the pathogenesis of type 2 diabetes and a cofactor in the

development of dyslipidemia, hypertension, and atherosclerosis.

Insulin resistance is present in more than 90% of people with type 2

diabetes and predates the development of hyperglycemia by many

years. Other components of the metabolic syndrome (ie,

hypertension, hypertriglyceridemia, and decreased HDL) are

themselves CAD risk factors and hyperglycemia further contributes

to vascular damage. Whether or not hyperinsulinemia and insulin

resistance directly contribute to vascular damage is controversial

and under active investigation.

The pathogenesis of CAD in diabetes is multifactorial. Metabolic

changes, oxidative stress and glycoxidation, endothelial

dysfunction, inflammation, and a diabetes associated prothrombotic

state all play a role in the cardiovascular complications of diabetes.

For example, current evidence suggests a pivotal role for

inflammation in all phases of atherosclerosis, from the formation of

fatty streaks to subsequent rupture of the lesions and acute coronary

syndromes. This concept is supported by epidemiological and

clinical studies where systemic inflammatory markers such as C–

reactive protein (CRP), interleukin-6 (IL-6), and serum amyloid A,

have been shown to be strong predictors of cardiovascular

complications in various settings. In addition to the potential use of

inflammatory biomarkers as risk predictors for cardiovascular

events, they might serve as targets for pharmacologic therapy.

Diabetes mellitus is also associated with poor outcomes after

vascular occlusion, compared with the nondiabetic population.

Plague composition is known to determine the risk of plaque

disruption and thrombosis, which is the main cause of acute

coronary syndrome. Plaques prone to rupture are characterized by

decreased collagen and vascular smooth muscle cells (VSMCs) in

their cap and shoulder regions, and a rich inflammatory infiltrate.

Artherosclerotic lesions of type 2 diabetic patients reveal greater

macrophage infiltration, larger lipid cores and decreased VSMC

content than lesions from non diabetic patients. Thus, type 2

diabetes is associated not only with accelerated and premature

coronary artherosclerosis, but also with an increased vulnerability

for plaque rupture and thrombosis.

The United Kingdom Prospective Diabetes Study demonstrated that

intensive blood glucose control with insulin or sulfonyiurea in type 2

diabetic subjects had only a limited effect an the incidence of

cardiovascular events indicating the necessity of new treatment

strategies to reduce cardiovascular morbidity and mortality associated

with this syndrome.

Thiazolidinediones and peroxisome proliferator activated

receptors

Thiazolidinediones (TZDs), a class of insulin sensitizing agents that

act as ligands for the nuclear receptor peroxisome proliferator activated

receptor gamma (PPAR-), are used frequently in the treatment of

patients who have type 2 diabetes. These drugs reduce peripheral

insulin resistance, characteristically found in type 2 diabetic patients,

by increasing insulin dependent glucose disposal and reducing hepatic

glucose output.

The first clinically used TZD, Troglitazone was withdrawn from the

market because of rare, but serious hepatotoxicity. Rosiglitazone

and pioglitazone, the two TZDs currently available are not

associated with any hepatotoxicity and are used widely for

treatment of type 2 diabetes. In addition to their effects on

carbohydrate metabolism, TZDs have beneficial effects on plasma

lipids. Both pioglitazone and rosiglitazone increase serum levels of

HDL and pioglitazone also markedly reduces plasma triglyceride

levels. In addition in numerous studies, TZDs and non TZD PPAR-

ligands have been found to attenuate atherosclerotic lesion

formation in animal models and reduce inflammatory gene

expression in vascular cells in vitro.

Role of peroxisome proliferator activated receptor gamma in

adipose tissue

Adipose tissue is an endocrine organ that releases proinflammatory

factors that promote vascular damage and atherosclerosis. Tumor

necrosis factor alpha (TNF-) inhibits insulin signaling, thereby

contributing to insulin resistance and activates multiple

proinflammatory pathways via NF-K. Leptin, produced by adipose

tissue, can alter insulin action and has been recognized recently to be

an important mediator of obesity related hypertension. In contrast,

visceral adipose tissue increases are associated with decreased

plasma adiponectin, a protein recently shown to have significant

antidiabetic and anti-atherogenic functions. Taken together, these

observations indicate that the adipocyte plays a central role in the

relationship between obesity, diabetes and CAD.

PPAR-, the molecular target of the TZD ligands, is expressed at high levels in adipose tissue, and is a central regulator of adipocyte gene expression and differentiation. Retroviral mediated expression of PPAR- stimulated adipose differentiation of cultured fibroblasts and several studies have demonstrated that PPAR- expression is necessary and sufficient to promote adipocyte cell differentiation in vivo and in vitro.

Although the mechanisms underlying the insulin sensitizing effects of TZDs are complex and not understood completely, adipose tissue is known to be an important target of TZDs. Activation of PPAR- in insulin resistant animals or humans results in an increase in the sensitivity of the liver to insulin mediated suppression of hepatic glucose production and the skeletal muscle to insulin mediated glucose uptake. These in vivo effects on insulin signaling are caused by the combined actions of PPAR- ligands on adipose tissue, liver and skeletal muscle.

PPAR- ligands profoundly alter gene expression in adipose tissue.

Resistin and TNF- expression, both of which induce insulin

resistance, are reduced by PPAR- ligands, suggesting that the

insulin sensitizing effects of PPAR- agonists are related to their

anti-inflammatory properties. In addition, expression and secretion of

adiponectin, a protein produced exclusively by the adipocyte, is

increased by PPAR- agonists both in vivo and in vitro. Altering pro

and anti-inflammatory protein secretion from adipose tissue thus

appears to be an important mechanisms whereby TZDs improve

insulin sensitivity in distant organs, and exert vasoprotective effects.

These data suggest that adipose tissue may be the primary target of

PPAR- ligands, resulting in improved insulin sensitivity in liver and

muscle.

However, in recent studies, PPAR- ligands were found to improve

insulin sensitivity in several different mouse models lacking adipose

tissue, indicating a beneficial effect outside the adipose tissue.

Consistent with these observations, mice deficient in skeletal muscle

or liver PPAR- expression have severe whole body insulin

resistance. Hevener and colleagues postulated that selective deletion

of PPAR- in skeletal muscle caused insulin resistance in muscle,

followed by impaired insulin action in adipose tissue and liver. In

contrast, Norris and colleagues found that in mice with muscle

specific deletion of PPAR-, insulin sensitivity in skeletal muscle

was normal, but was impaired in the liver. Many of the differences in

the mouse studies may depend on strain differences.

Role of peroxisome proliferator activated receptor gamma in

inflammation and atherosclerosis

In addition to adipose tissue, liver and skeletal muscle, PPAR- is

expressed in VSMCs, endothelial cells, macrophages and T cells,

where it plays an important role in regulating inflammatory

responses. PPAR- specific ligands inhibit the production of a host

of inflammatory cytokines, such as TNF-, IL-1- and IL-6 in

monocytes, inducible nitric oxide synthase, endothelin –1 and

interferon inducible protein 10 (IP-10) in endothelial cells.

Moreover, PPAR- agonists have been shown to decrease the

expression of the adhesive, proinflammatory molecule.

In various studies, PPAR- ligands have been shown to decrease

atherosclerotic lesion formation in genetically prone mouse models.

This effect occurs in insulin sensitive and insulin resistant models

with or without diabetes. Female mice demonstrate proportionally

less attenuation of atherosclerosis upon PPAR- ligand treatment

than male mice, indicating that additional factors such as hormonal

status may affect the outcome. PPAR- ligands also inhibited

angiotensin II (Ang II) accelerated atherosclerosis in mice without

effects on lipid profile, glucose, or blood pressure. The attenuation

of Ang II-accelerated artherosclerosis correlated with a

downregulation of the proinflammatory transcription factor early

growth response gene 1 (Egr-1) and several of its target genes,

indicating that inhibition of inflammation plays a crucial role for the

antiatherosclerotic effect of PPAR- ligands.

Ang II is known to be a major proatherogenic factor that induces

inflammation in the vessel wall and stimulates proliferation and

migration of VSMCs and monocytes. Previous studies have shown

that PPAR- ligands modulate Ang II signaling both at the receptor

level and downstream of the Ang II type 1 receptor (AT(1)-R).

PPAR- activators have been found to downregulate AT(1)-R

expression in VSMC and block AT(1)-R mediated mitogen

activated protein kinase activation, which is crucial for VSMC

proliferation and migration.

Results from the first TZD cardiovascular outcome trial,

Prospective Pioglitazone Clinical Trial in Macrovascular Events

(PROactive), were published recently. In this prospective double

blind, randomized placebo-controlled, secondary prevention study,

pioglitazone treatment was found to reduce the composite of all

cause mortality, nonfatal myocardial infarction, and stroke in type 2

diabetic subjects. Clinical trials examining shorter term surrogate

end points for atherosclerosis have revealed that TZD treatment

improves measures of carotid intimal medial thickness. TZDs may

also improve endothelial reactivity. The author’s group recently

demonstrated that rosiglitazone treatment improved positron

emission tomography assessed myocardial blood flow responses

test, which is largely endothelial dependent.

In addition, various studies have shown that treatment of subjects

with type 2 diabetes with TZDs reduced inflammatory surrogate

parameters of atherosclerosis, such as CRP, TNF- serum amyloid

A and plasminogen activator inhibitor type 1 (PAI-1), while

increasing adiponectin. Although these effects where observed as

early as 2 weeks after treatment. TZDs exhibit maximal glucose

lowering effects 8 to 12 weeks after treatment. Sato and colleagues

observed that pioglitazone treatment reduced CRP levels in both

responders and nonresponders with respect to its antidiabetic effect.

These findings suggest that the effect of TZDs on the biomarkers of

cardiovascular risk may be independent of their antidiabetic actions.

Previous data indicate that throughout the spectrum of insulin

resistance from the metabolic syndrome to type 2 diabetes PAI-1

levels are increased.

Because PAI-1 promotes clot formation in plasma and various

studies have demonstrated an association between circulating PAI-1

levels and cardiovascular events, a TZD mediated decrease in PAI-

1 might play an important role in reducing the incidence of CAD

and its complications in this population.

Role of peroxisome proliferator activated receptor gamma in

restenosis

VSMC activation, migration and proliferation not only play

decisive roles in the development of atherosclerosis, but are also the

primary pathophysiologic mechanism for the failure of procedures

used to treat occlusive proliferative atherosclerotic diseases, such as

postangioplasty restenosis, transplant vasculopathy, and vein bypass

graft failure.

Patients who have diabetes are at increased risk not only for the

development of CAD, but also have an elevated risk of developing

postangioplasty restenosis compared with individuals who do not have

diabetes. In response to vascular injury endothelial cells. VSMCs and

macrophages secrete cytokines and growth factors that perpetuate the

vasculoproliferative response.

PPAR- ligands have been shown to inhibit proliferation and

migration of VSMCs in vivo. The antiproliferative activity of PPAR-

ligands appears to result from their ability to inhibit retinoblastoma

protein (Rb) phosphorylation by modulating the expression of several

key cell cycle regulators that control G1 S phase progression.

Inhibition of VSMC growth and migration by PPAR- ligands in vitro

turns into an in vivo alteration of neointima formation.

In animal models of restenosis, TZDs have been shown to inhibit

intimal hyperplasia after mechanical injury in both insulin sensitive

and insulin resistant animals. Moreover, early clinical trials of subjects

with type 2 diabetes have demonstrated that both pioglitazone and

rosiglitazone have a potent inhibitory effect of neointimal tissue

formation after coronary stent implantation.

Summary

Obesity and diabetes mellitus, significant risk factors for the

development of CAD, are becoming a global epidemic. Currently,

CAD is the leading cause of death. Despite significant improvements

in the management of diabetes, type 2 diabetes mellitus remains a risk

equivalent for CAD. A type 2 diabetic patients has the same risk of a

future cardiovascular event as a nondiabetic individual who has had a

prior myocardial infarction.

New treatment strategies are needed urgently to reduce diabetes associated cardiovascular morbidity and mortality.

TZDs have demonstrated some cardiovascular benefits in early trials, and theoretically may improve cardiovascular disease risk through several mechanisms. PPAR- ligands have been shown to attenuate inflammatory responses, which have been shown to be associated with both insulin resistance and atherosclerosis. Inhibition of VSMC proliferation and migration, fundamental processes involved in atherosclerosis and restenosis, may contribute further to the potential cardiovascular benefit of these ligands.

Although current TZD PPAR- ligands may have significant potential benefits in the treatment of type 2 diabetes, these must be offset against potentially serious side effects. In clinical trials, both pioglitazone and rosiglitazone have been associated with fluid retention, hemodilution, weight gain, and congestive heart failure (CHF).

The observed, normally modest weight gain is explained by fluid

retention, increased adipogenesis and a net flux of fatty acids into

adipose tissue. However, these side effects were more apparent when

TZDs were used in combination with insulin, and appeared to

correlated with drug dosage. For example, rosiglitazone (4 to 8 mg/d)

added to insulin therapy resulted in CHF rates of 2% and 3%

respectively compared with a rate of 1% in the group treated with

insulin alone. Thus, according to American Heart Association and

American Diabetes Association guidelines, TZDs should not be used in

patients who have NHYA class III and IV CHF. Another potential

concern is the possibility that TZDs may promote tumorigenesis or

tumor growth, because PPAR- ligands have been shown to increase

the frequency and size of colon tumors in mice. However, PPAR-

agonists have also been shown to cause a significant reduction in the

growth of human cancer cell lines.

Extrapolation of the evidence of carcinogenesis from rodents to

humans is an uncertain process, and further studies are necessary.

The vascular effects of TZDs and their beneficial activity against

multiple proinflammatory and prothrombotic factors provide a

compelling rationale for conducting cardiovascular outcomes trials

with these oral antidiabetic agents. In clinical studies, TZD treatment

has been found to decrease carotid intimal medial wall thickness in

type 2 diabetic subjects at 3 and 6 month end points. In addition,

clinical trials have shown that after coronary stent implantation, type 2

diabetics who received TZDs had a significant reduction in restenosis,

compared with a control group who received equal glucose lowering

therapy with other agents. Results from the first TZD cardiovascular

outcome trial.

Proactive, demonstrated that pioglitazone reduced the risk of all

cause mortality myocardial infarction (excluding silent myocardial

infarction), and stroke in subjects with type 2 diabetes. The

cardiovascular outcomes trials RECORD (Rosiglitazone Evaluation

for Cardiac Outcomes and Regulation of Glycemia in Diabetes) and

BARI-2D (Bypass Angioplasty Revascularization Investigation in

Type 2 Diabetes), using rosiglitazone, will help to determine

whether the vascular and metabolic effects of PPAR- ligands can

protect persons with type 2 diabetes from the increased

artherothrombolic risk associated with that disease.

Airway smooth muscle as a Target for Asthma therapy

Julian Solway, M.D. and Charles G. Irvin, Ph.D.Department of Medicine, University of Chicago

The precise role of airway smooth muscle in the pathogenesis of

asthma remains uncertain. The contraction of airway smooth muscle

certainly causes acute narrowing of the airway and airflow

obstruction in asthma, and smooth muscle mass in increased in

asthmatic airways.

However, whether airway smooth muscle generates sufficient force

in vivo to account for the excessive airway obstruction that

characterizes asthma is unknown.

Abnormalities in the dynamics of contraction in the capacity of

smooth muscle to maintain shortening in the face of load

fluctuations imposed by tidal breathing or in the capacity to relax

represent other important mechanisms by which airway smooth

muscle might contribute to airway narrowing in asthma. Beyond

these mechanical effects, airway smooth muscle probably

contributes to inflammation of the airway by secreting cytokines,

modifying the tissue matrix, binding migratory inflammatory cells

or all three. Whatever its role in asthma may be, it seems clear that

airway smooth muscle could not contribute to asthma pathogenesis

if it were absent.

In this issue of the Journal, Cox and colleagues report a clinical

benefit of a novel approach to asthma therapy – bronchial

thermoplasty. In this procedure, during three separate treatment

visits, radiofrequency current is applied to the walls of the central

airways through a brochoscopically placed probe. Studies in

animals and humans have shown that such treatment reduces the

airway smooth muscle mass but causes epithelial damage that

resolves over time. In patients with moderately severe asthma,

bronchial thermoplasty reduced airway responsiveness to an inhaled

constrictor and modestly increased flow rates – effects that

persisted for at least a year.

The study by Cox and colleagues extends those findings by

showing improvements in symptoms and quality of life and by

reducing the use of rescue medication in subjects with moderate or

severe asthma during periods when long acting 2-adrenergic

agonists were withdrawn. That these effects occurred without

significant increases in the forced expiratory volume in 1 second or

a reduction in airway hyperresponsiveness suggests either that

smooth muscle mediated airway constriction beyond the central

airways accessible on bronchoscopy is clinically important or that

mechanisms independent of airway smooth muscle, such as airway

closure, contribute to airflow obstruction in subjects with asthma.

The mechanism underlying the effect of bronchial thermoplasty in

asthma has not been fully, established and might include changes

other than the loss of airway muscle. For example conceivably,

bronchial thermoplasty alters properties of airway epithelium,

mucus glands, nerves, or blood vessels or modifies the character of

airway inflammation in such a way that asthma related symptoms

are reduced as a result of either alterations in airway sensation or a

genuine reduction in steady or episodic airway narrowing. What

seems certain, however, is that bronchial thermoplasty reduces the

smooth muscle mass in the airway wall. This well documented

effect, together with the beneficial clinical effects suggested in the

report by Cox and colleagues and in previous studies, highlights the

potential usefulness of targeting airway smooth muscle in the

treatment of asthma.

Indeed, a number of current treatments already, exert some beneficial effects by acting on airway smooth muscle. Inhaled 2-agonists often

relax airway smooth muscle and can enhance the nuclear entry of glucocorticoids, thereby potentiating their anti-inflammatory effect. Glucocorticoids inhibit the proliferation and migration or airway myocytes and suppress their expression of a number of proinflammatory cytokines. Anti-IgE antibody might also modulate the function of airway smooth muscle, since the low affinity IgE receptor is expressed on airway smooth muscle and sensitization with IgE increases its force generation, impairs relaxation, and stimulates cytokine production. Furthermore, exposure to serum from persons with atopy increases the velocity of contraction of human bronchial rings, this increased velocity is thought to enhance the shortening of airway smooth muscle and to confer resistance to the relengthening of the muscle induced by force fluctuations. Perhaps anti-IgE antibody also prevents these phenomena.

Bronchial thermoplasty represents a novel approach to targeting airway

smooth muscle, but it ablates airway myocytes only in bronchi 3 mm

or larger in diameter, which can be treated directly. For this reason,

and because of the considerable effort involved (three separate

bronchoscopic procedures, each with a small but significant risk of

complications), notable adverse effects (in the short term, at least) and

likely expense, bronchial thermoplasty will probably need further

refinement if it is to emerge as a widely applicable, practical treatment

for moderate or severe asthma. Nonetheless, the results reported by

Cox and colleagues suggest that we should now contemplate other

approaches to targeting airway smooth muscle that might prove to be

less invasive, more practical and more amenable to application

throughout the airways.

Among the approaches envisioned is the possibility of ridding the

airways of smooth muscle by stimulating apoptosis of airway

myocytes. Alternatively, since many of the genes encoding smooth

muscle contractile apparatus proteins require a common, relatively

muscle specific transcription factor (serum response factor) for

transcriptional activation, it might be possible to antagonize the

activity of the serum response factor and in that way shut down

expression of the contractile apparatus. Depletion of contractile

proteins should prevent smooth muscle mediated airway constriction

and thus might prevent the occurrence of acute asthma attacks.

Another approach to preventing contraction might be to attack the

integrity of contractile filaments (e.g. destroying actin filaments by

activating cofilin, an acting binding protein that depolymerizes

filamentous actin) or to block the linking of contractile myofilaments

to focal adhesions at the cell surface, thereby preventing the

transmission of the contractile force generated within each myocyte to

the surrounding tissue. Finally, ways might be discovered to magnify

the antiobstructive effect of tidal breathing, in which fluctuations in the

tidal force transmitted through parenchyma- airway interactions

relengthen shortened airway smooth muscle even during continued

contractile stimulation. An airway that cannot remain constricted for

long cannot cause prolonged airflow obstruction.

In medicine, pioneering approaches have often been replaced by

other approaches with similar goals but better means of

implementation. Vagotomy, for example, which was performed to

reduce acid secretion in peptic ulcer disease, has been replaced by

treatment with H2 receptor antagonists and proton pump inhibitors,

which also reduce acid secretion. We expect that bronchial

thermoplasty may refined to become more effective and more

practically applicable, but we also hope that the lessons it has

already taught will prompt the development of other novel

approaches that target the contribution of airway smooth muscle to

the pathogenesis of asthma.

The evolving role of MRI in the detection and evaluation of breast cancer

Robert A, Smith Ph.D.American Cancer Society, Atlanta

The age adjusted rate of death from breast cancer in the United States

was 24% lower in 2003 than it was in 1989. A decline that has been

attributed principally to both the role of mammography in detecting

early stage tumors and improvements in therapy. Indeed, early

diagnosis and therapy have been the cornerstone of efforts to control

breast cancer, since a readily accessible preventive strategy for women

with an average risk has been elusive. Prevention is clearly the

preferable strategy for controlling cancer, but for the foreseeable

future, the control of breast cancer will depend mostly on early

detection, careful diagnostic evaluation and therapy.

The introduction and widespread use of mammography for the

early detection of breast cancer is one of the most important

recent achievements in the control of cancer. Mammography is

the study of breast using X-ray. The actual test is called a

Mammogram. There are two types of mammograms – a

screening mammogram is ordered for women who have no

problems with their breasts. It consists of two x-ray views of

each breast. A diagnostic mammogram is for evaluation of

new woman with breast cancer treated with lumpectomy.

The prognostic value of detecting breast cancer while it is still localized to the breast exceeds what can be achieved with therapy when breast cancer is advanced and over the past decade the trend toward a more favorable stage at diagnosis has played a major role in the reduction of the rate of death due to breast cancer.

Although the association is difficult to measure, it is likely that ultrasonography, magnetic resonance imaging (MRI) and digital mammography also improve the outcome when they are used as a substitute for women in whom conventional mammographic screening has not been useful. For example, digital mammography has recently been shown to be a more effective imaging tool in younger women and in women with heterogeneously or extremely dense breasts. It is well established that conventional film mammography does not identify all breast cancer and those other imaging methods can detects tumors that are occult on mammography or can provide more information about findings that were inconclusive with conventional imaging.

Once breast cancer has been detected, the importance of thorough and

accurate breast imaging is paramount, because multicentric breast

cancer may preclude breast conserving strategies, and the detection of

a synchronous, contralateral primary tumor may affect choices

regarding surgery and reconstruction. The risk of local recurrence is a

dark cloud that hangs over patients with newly diagnosed breast cancer

and longer term survivors, despite reassurances that multicentric or

multifocal disease that may present, but not visible, can effectively

treated by whole breast irradiation and adjuvant therapy. Even with

this reassurance, it is likely that most women would prefer the

detection of such mammographically invisible lesions so that they

could be factored into decision making with regard to treatment. For

this reason, a growing proportion of patients with newly diagnosed

breast cancer are undergoing further evaluation with MRI.

In this issue of the Journal, Lehman and colleagues report the results of their study of the effectiveness of MRI in the detection of cancer in the contralateral breast after negative clinical and mammographic findings in women with newly diagnosed breast cancer.

Among 969 study participants, MRI of the contralateral breast was performed within 60 days after the diagnosis of unilateral breast cancer and within 90 days after clinical and mammographic breast examination.

Among 33 patients in whom breast tumors were diagnosed in the contralateral breast during the 12 months follow up period, 30 tumors (invasive tumors in 18 women and ductal carcinoma in situ in 12) were detected by means of MRI. Thus, the additional diagnostic yield of MRI was 3.1% after negative findings on mammographic and clinical breast examination, with 91% sensitivity and 88% specificity.

As Lehman and colleagues note, the very high negative predictive

value of MRI can be reassuring to women whose concern about the

presence of undetected disease leads them to seek prophylactic

mastectomy of the contralateral breast. The authors also note the

advantage of treating synchronous cancers simultaneously, thus

avoiding another round of therapy at a later time when the tumour in

the contralateral breast would be detected by means of conventional

imaging or on the basis of symptoms. There may be arguments that

the added sensitivity of MRI of the contralateral breast comes at high

cost in terms of false positive results and overdiagnosis due to the

high rate of detection of ductal carcinoma in situ. Nevertheless, the

false positive rate and the predictive value of a positive test are in an

acceptable range, and there is little persuasive evidence that most

cases of ductal carcinoma in situ are not progressive.

Therefore, there is a value in detecting and treating malignant tumors

in the contralateral breast that were not identified by means of

mammography and clinical breast examination.

The responsible use of MRI for the evaluation of the breast is focused

primarily on patients with a high probability of breast cancer, and it

includes screening in women who are known or likely carriers of a

BRCA1 and BRCA2 mutation. The American College of Radiology’s

practice guideline for the performance of breast MRI outlines 12

clinical applications of MRI in the evaluation of breast disease.

Coincident with this issue of the Journal, the American Cancer

Society is publishing new recommendations for breast cancer

screening in women at high risk for breast cancer.

In the 2003 update to its guidelines for breast cancer screening, the

American Cancer Society stated that women at increased risk for

breast cancer might benefit from the earlier initiation of screening,

shorter screening intervals, or the addition of screening methods such

as breast ultrasound or MRI. On the basis of newer evidence, as well

as requests from clinicians for greater guidance in the use of breast

MRI, the guidelines now recommends annual breast cancer screening

by means of MRI for women with approximately 20% or greater life

time risk of breast cancer, according to risk models that are largely

dependent on a strong family history of breast or ovarian cancer.

Annual MRI screening is also recommended for women who have

undergone radiotherapy to the chest for Hodgkin’s disease.

The updated guideline also states that there is insufficient evidence

to make a recommendation for or against MRI screening in women

with a personal history of breast cancer, carcinoma in situ, or

atypical hyperplasia or in women with extremely dense breasts.

This year, the American College of Radiology is likely to initiate a

voluntary accreditation program for breast MRI that is similar to its

current programs for mammography and breast ultrasonography.