Journal club

1. Peroxisome Proliferator Activated Receptor Gama
Agonists : Their Role as Vasoprotective Agents in
Diabetes
Airway smooth
therapy
Florian Blaschke, MD, Evren MD, Willa A, MD
muscle
as
a
Target
for
Asthma
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.
Dr. Awadhesh Kr. Sharma

2. Peroxisome Proliferator Activated Receptor
Gama Agonists : Their Role as Vasoprotective
Agents in Diabetes
Florian Blaschke, MD, Evren MD, Willa A, MD
Department 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.

3. 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)

4. 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.

5. 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.

6. 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.

7. 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
receptors
and
peroxisome
proliferator
activated
Thiazolidinediones (TZDs), a class of insulin sensitizing agents that
act as ligands for the nuclear receptor peroxisome proliferator activated
receptor gamma (PPAR-γ), 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.

8. 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 PPARγ ligands have been found to attenuate atherosclerotic lesion
formation in animal models and reduce inflammatory gene
expression in vascular cells in vitro.

10. 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-α) inhibits insulin signaling, thereby
contributing
to
insulin
resistance
and
activates
multiple
proinflammatory pathways via NF-Kβ. 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.

11. PPAR-γ, 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-γ stimulated adipose differentiation of cultured fibroblasts and
several studies have demonstrated that PPAR-γ 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-γ 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-γ ligands on adipose tissue, liver and
skeletal muscle.

12. PPAR-γ ligands profoundly alter gene expression in adipose tissue.
Resistin and TNF-α expression, both of which induce insulin
resistance, are reduced by PPAR-γ ligands, suggesting that the
insulin sensitizing effects of PPAR-γ 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-γ 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-γ ligands, resulting in improved insulin sensitivity in liver and
muscle.

13. However, in recent studies, PPAR-γ 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-γ expression have severe whole body insulin
resistance. Hevener and colleagues postulated that selective deletion
of PPAR-γ 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-γ, 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.

14. Role of peroxisome proliferator activated receptor gamma in
inflammation and atherosclerosis
In addition to adipose tissue, liver and skeletal muscle, PPAR-γ is
expressed in VSMCs, endothelial cells, macrophages and T cells,
where it plays an important role in regulating inflammatory
responses. PPAR-γ specific ligands inhibit the production of a host of
inflammatory cytokines, such as TNF-α, IL-1-β and IL-6 in
monocytes, inducible nitric oxide synthase, endothelin –1 and
interferon inducible protein 10 (IP-10) in endothelial cells.
Moreover, PPAR-γ agonists have been shown to decrease the
expression of the adhesive, proinflammatory molecule.

17. In various studies, PPAR-γ 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-γ ligand treatment
than male mice, indicating that additional factors such as hormonal
status may affect the outcome. PPAR-γ 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-γ ligands.

18. 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-γ ligands modulate Ang II signaling both at the receptor
level and downstream of the Ang II type 1 receptor (AT(1)-R).
PPAR-γ 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.

20. 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.

21. 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-α 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.

22. 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 PAI1 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.

23. 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-γ ligands have been shown to inhibit proliferation and migration
of VSMCs in vivo. The antiproliferative activity of PPAR-γ 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-γ ligands in vitro
turns into an in vivo alteration of neointima formation.

24. 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.

25. 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-γ 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-γ 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).

26. 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-γ ligands have been shown to increase
the frequency and size of colon tumors in mice. However, PPAR-γ
agonists have also been shown to cause a significant reduction in the
growth of human cancer cell lines.

27. 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.

28. 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-γ ligands can
protect persons with type 2 diabetes from the increased
artherothrombolic risk associated with that disease.

29. 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.

31. 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.

32. 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.

33. 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 β2-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.

37. 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.

38. Indeed, a number of current treatments already, exert some beneficial
effects by acting on airway smooth muscle. Inhaled β2-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.

39. 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.

40. 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.

41. 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.

42. 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.

43. 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.

44. 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.

47. 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.

48. 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.

49. 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.

52. 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.

53. 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.

54. 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.

55. 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.