Breast Cancer

Warner E, Plewes DB, Hill KA, et al. Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. JAMA. 2004;292:1317-25. [PMID: 15367553] [Abstract/Free Full Text]

Women with mutations of the BRCA1 and BRCA2 genes have a lifetime breast cancer risk of 50% to 85%. Routine mammography detects approximately 50% of tumors in women with the mutation versus 75% of tumors in women who do not have the mutation (1). Decreased sensitivity of mammography in BRCA1 and BRCA2 mutation carriers is the result of several factors. BRCA1 and BRCA2 mutation carriers are more likely to develop breast cancer at younger ages, when dense breast tissue makes tumors more difficult to detect. In addition, breast cancer in patients with BRCA1 is less likely to be associated with microcalcifications and more likely to have round margins, making it more difficult to identify by mammography.

This study compared the sensitivity and specificity of mammography, magnetic resonance imaging (MRI), ultrasonography, and clinical breast examination in 263 Canadian women with BRCA1 or BRCA2 mutations. The women, who ranged in age from 25 to 65 years, underwent 1 to 3 annual examinations with 3 modalities: mammography, MRI, and ultrasonography. Clinical breast examination was also performed on the day of screening and at 6-month intervals.

Of 22 detected tumors (16 invasive and 6 ductal carcinoma in situ), 17 (77%) were detected by MRI, 8 (36%) by mammography, 7 (33%) by ultrasonography, and 2 (9%) by clinical breast examination. After initial screening with MRI, 26% of the study participants were recalled for further diagnostic evaluation, consisting of immediate diagnostic MRI or close follow-up with a 6-month interval MRI. Seven tumors were detected by MRI but missed by all other modalities. Two tumors were detected by ultrasonography alone, and 2 tumors were detected by mammography alone. One interval case of cancer (detected between study evaluations) was identified with all modalities at the time of diagnosis; retrospective analysis revealed that the tumor had also been visible on previous MRI and mammography.

On the basis of biopsy rates, the sensitivity and specificity for the detection of breast cancer were 77% and 95.4% for MRI, 36% and 99.8% for mammography, 33% and 96% for ultrasonography, and 9.1% and 99.3% for clinical breast examination.

In conclusion, MRI was more sensitive than ultrasonography, mammography, or clinical breast examination alone in this group of women with BRCA1 and BRCA2 mutations. No modality detected all of the tumors. The use of all 4 modalities had greater sensitivity than the traditionally recommended combination of mammography and clinical breast examination, but one fourth of patients who underwent MRI required additional testing after the first evaluation to better discriminate suspicious lesions. Including ultrasonography in the protocol decreased specificity because of additional biopsies; however, eliminating ultrasonography decreased sensitivity from 95% to 86%. Whether surveillance regimens that include MRI and ultrasonography reduce mortality from breast cancer in high-risk women is unknown.

This study added to a growing body of literature that suggests MRI and ultrasonography improve cancer detection in women with BRCA mutations. The American Cancer Society recommends that women with BRCA mutations talk with their physicians about the benefits and limitations of undergoing mammography when they are younger, having additional tests (such as breast ultrasonography or MRI), or having more frequent clinical breast examinations (2). Some insurance carriers already offer coverage for enhanced screening of women at high genetic risk for breast cancer. Ideally, women with BRCA1 and BRCA2 mutations should be enrolled in clinical trials of screening protocols.

The value of enhanced screening remains debatable for women who do not have BRCA mutations. Until more studies are done, most experts would not recommend MRI or ultrasonography in women with lesser degrees of breast cancer risk (3, 4). The false-positive rate of MRI is unacceptably high in women at average risk for breast cancer. Screening ultrasonography is not recommended for women who are not at increased risk for breast cancer (2, 5).

Exemestane Therapy after 2 to 3 Years of Tamoxifen Therapy Improved Survival Compared with 5 Years of Tamoxifen Therapy Alone

Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350:1081-92. [PMID: 15014181] [Abstract/Free Full Text]

For many years, experts agreed that most postmenopausal women with early-stage, estrogen receptor–positive tumors should receive tamoxifen (a selective estrogen-receptor modulator) as adjuvant therapy for 5 years. On the basis of recent studies, however, the American Society of Clinical Oncology has changed this recommendation. New guidelines now state that "optimal adjuvant hormonal therapy for a postmenopausal woman with breast cancer includes an aromatase inhibitor as initial therapy or after treatment with tamoxifen" (6). Aromatase inhibitors, which inhibit or inactivate an enzyme that catalyzes the conversion of androgens to estrogens, profoundly reduce systemic estrogen levels in postmenopausal women. In this trial, Coombes and associates wanted to determine if, after 2 to 3 years of tamoxifen therapy, switching patients to an aromatase inhibitor (exemestane) was more effective than continuing tamoxifen for the remaining 5 years of treatment.

In a randomized, double-blind trial, 4742 patients were initially treated with tamoxifen. After a median duration of 2.4 years of tamoxifen therapy, 2362 women were randomly assigned to switch to exemestane while 2380 women continued to receive tamoxifen. The primary end point was disease-free survival. After a median follow-up of 30.6 months, the unadjusted hazard ratio for local or metastatic recurrence, contralateral breast cancer, or death was 0.68 for the exemestane group (95% CI, 0.56 to 0.82). Three years after randomization, the absolute benefit of exemestane on disease-free survival was 4.7% (CI, 2.6% to 6.8%). Exemestane use was associated with a higher incidence of arthralgia and diarrhea. Tamoxifen use was associated with a higher incidence of thromboembolic events, gynecologic symptoms (including vaginal bleeding), and muscle cramps.

In addition to the adverse effects reported in this paper, studies of aromatase inhibitors have consistently shown that the risk for osteoporosis and fracture is increased compared with placebo or tamoxifen (7-9). According to American Society of Clinical Oncology guidelines, women should undergo a baseline bone mineral density evaluation before beginning treatment with aromatase inhibitors. Bisphosphonate therapy should be prescribed for breast cancer patients with osteoporosis. Women taking aromatase inhibitors who are not being treated for osteoporosis should undergo annual bone mineral density screening (10).

With the availability of another choice of adjuvant therapy, medical oncologists and patients must work together to determine which drugs are most appropriate on the basis of individual patient characteristics. Breast cancer survivors who are taking tamoxifen (or who have recently completed tamoxifen therapy) and are being followed by general internists may need to be re-referred to oncologists for consideration of additional therapy.

Ovarian Cancer

Goff BA, Mandel LS, Melancon CH, et al. Frequency of symptoms of ovarian cancer in women presenting to primary care clinics. JAMA. 2004;291:2705-12. [PMID: 15187051] [Abstract/Free Full Text]

Ovarian cancer is the fifth leading cause of cancer deaths among women in the United States. The usefulness of serial pelvic ultrasonography and serum CA-125 tumor marker testing has been investigated, but the American College of Physicians, the American College of Obstetricians and Gynecologists (ACOG), and the U.S. Preventive Services Task Force all recommend against routine screening of the general population because of lack of effectiveness and high rates of false-positive results (11-13).

Women with symptoms of ovarian cancer often present first to physicians other than gynecologists, particularly general internists. In a recent retrospective study of 1725 women in the United States and Canada, 45% of ovarian cancer patients who were surveyed reported that cancer was diagnosed more than 3 months after an initial consultation with a health care provider for associated symptoms (14). Diagnosis at an earlier stage is highly correlated with better survival (15), and recent studies suggest that many women with earlier stage disease are symptomatic (14, 16-18).

This prospective, case–control study compared the frequency, severity, and duration of symptoms of 1709 women who visited a primary care clinic with those of 128 women known to have pelvic masses. All participants completed an anonymous survey of symptoms experienced during the previous 12 months; the latter group was surveyed before surgery to determine if the mass was benign (n = 84) or malignant (n = 44). Compared with clinic controls, women with malignant pelvic masses (ovarian cancer) had an odds ratio of 7.4 (CI, 3.8 to 14.2) for increased abdominal size, 3.6 (CI, 1.8 to 7.0) for bloating, 2.5 (CI, 1.3 to 4.8) for urinary urgency, and 2.2 (CI, 1.2 to 3.9) for pelvic pain. Women with cancer typically experienced symptoms 20 to 30 times per month and had more symptoms of higher severity and more recent onset than women with benign pelvic masses or controls. The combination of bloating, increased abdominal size, and urinary urgency was found in 43% of women with ovarian cancer but only 8% of women presenting to primary care clinics. These symptoms were also significantly more common in women with ovarian cancer than in those with irritable bowel syndrome (odds ratio, 5.4 [CI, 2.4 to 12.2]).

On the basis of these findings, ovarian cancer should be strongly considered in the differential diagnosis for women with increased abdominal size, bloating, urinary urgency, and pelvic pain. Symptoms that are not associated with menses, or that begin after menopause, are more likely to be the result of ovarian pathology. Physicians should particularly suspect pathologic ovarian conditions when symptoms are frequent, severe, or of recent onset or if several symptoms are present. Clinicians evaluating patients with these symptoms should obtain a detailed history and perform a physical examination that includes a pelvic examination. Transvaginal pelvic ultrasonography is usually the initial test of choice when ovarian cancer is suspected.

Cervical Cancer

Sirovich BE, Welch HG. Cervical cancer screening among women without a cervix. JAMA. 2004;291:2990-3. [PMID: 15213211] [Abstract/Free Full Text]

Twenty-one percent of U.S. women older than 18 years of age have undergone hysterectomy. The American Cancer Society, ACOG, and the U.S. Preventive Services Task Force endorse omitting Papanicolaou testing for women who have had hysterectomy except in cases in which the cervix was spared or the patient had cervical neoplasia (2, 13, 19). Experts have suspected that these recommendations are often not followed in clinical practice.

In 1996, the U.S. Preventive Services Task Force recommended that cervical cancer screening was unnecessary for most women after hysterectomy. This study aimed to determine whether Papanicolaou testing decreased among women who have undergone hysterectomy after that recommendation. The study used data obtained between 1992 and 2002 by the Behavioral Risk Factor Surveillance System, an annual population-based telephone survey of U.S. adults conducted by the Centers for Disease Control and Prevention. Each year of the survey included a representative sample of women (18 years of age or older) who had undergone hysterectomy. The study included a total of 188 390 patients. Data were also obtained from other sources that identified the timing, type, and indication for hysterectomy.

In 2002, 69.1% of women who had undergone hysterectomy reported having had a Papanicolaou test within the past 3 years; in comparison, 68.5% of women surveyed in 1992 reported that they had undergone Papanicolaou testing within the past 3 years. After accounting for Papanicolaou tests performed before recent hysterectomy, hysterectomies that spared the cervix, and for hysterectomies performed for management of cervical neoplasia, the investigators estimated that approximately 10 million U.S. women are screened unnecessarily. Because time spent on cervical cancer screening could be shifted to other more productive preventive measures, physicians who adhere to the accepted recommendations could conserve financial resources and improve preventive care for millions of women.

In order to implement these guidelines, it is important that internists who care for patients who have had hysterectomy determine the reason for hysterectomy and whether the cervix was spared. Patients may be uncertain whether they had cervix-sparing surgery, and records may be unavailable. In these cases, pelvic examination is indicated to determine whether the cervix remains.

Internists often ask about the need for screening pelvic examinations in patients who are no longer receiving cervical cancer screening. Unfortunately, major organizations disagree on the approach to such patients. No research has demonstrated a benefit for continuing to perform pelvic examinations in this setting. On the basis of expert opinion, however, ACOG still recommends annual pelvic examination. For patients whose ovaries were spared, the American Cancer Society recommends "periodic" examination of the ovaries, while the U.S. Preventive Services Task Force does not recommend pelvic examination for the purpose of screening for ovarian cancer (2, 5, 19).

Heart Disease

Mosca L, Appel LJ, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation. 2004;109:672-93. [PMID: 14761900] [Free Full Text]

An expert panel recently convened to develop evidence-based guidelines for the prevention of heart disease in women. The panel consisted of representatives from the American Heart Association; American College of Cardiology; American College of Nurse Practitioners; ACOG; American College of Physicians; American Medical Women's Association; Association of Black Cardiologists; Centers for Disease Control and Prevention; National Heart, Lung, and Blood Institute; National Institutes of Health Office of Research on Women's Health; Society of Thoracic Surgeons; and the World Heart Federation. To formulate their guidelines, the group examined high-quality studies that focused on major clinical end points; secondary outcomes, such as quality of life and resource utilization, were excluded.

The panel endorsed a 5-point strategy for cardiovascular disease prevention in clinical practices:

1. Assess all women and categorize their risk level as high, intermediate, lower, or optimal based on Framingham data. An absolute coronary heart disease risk calculator is available online and for download for use in personal computers and personal digital assistants at http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm.

2. Recommend lifestyle approaches for all women, including smoking cessation; regular exercise consisting of 30 minutes of moderate-intensity physical activity on most or all days of the week; weight management to achieve a body mass index of 18.5 to 24.9 kg/m² and a waist circumference of less than 35 inches; and a diet that limits intake of trans fat, saturated fat to less than 10% of calories, and cholesterol intake to fewer than 300 mg/d.

3. Provide other cardiovascular disease prevention interventions as indicated, including lifestyle and pharmacologic control of hypertension, lipid abnormalities, and diabetes.

4. When appropriate, provide risk intervention according to risk level, including aspirin or clopidogrel therapy, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, ß-blockers, and statin therapy for all women with coronary artery disease unless contraindicated. Other women at high risk, including those with diabetes; chronic renal disease; and carotid artery disease, abdominal aortic aneurysm, or peripheral vascular disease, should be treated with aspirin or clopidogrel and statins, regardless of cholesterol levels.

A controversial subject is the appropriate time to initiate pharmacologic treatment of lipid abnormalities in a population that has not been adequately studied in randomized, controlled clinical trials—women at intermediate and lower risk for coronary artery events (20, 21). This guideline provided a consensus statement of current expert opinion on the topic. Women at intermediate risk have a 10-year absolute coronary heart disease risk of 10% to 20%. These women generally have multiple risk factors or a markedly elevated single risk factor, such as family history of first-degree relatives with early-onset coronary heart disease (age <55 years in men and <65 years in women). For women at intermediate risk, statin therapy is recommended if the low-density lipoprotein cholesterol level is 3.37 mmol/L (130 mg/dL) or greater after lifestyle changes are instituted. Pharmacotherapy with statins is recommended for women at less than 10% 10-year risk for coronary heart disease events at a serum low-density lipoprotein cholesterol level of 4.14 mmol/L (160 mg/dL) if they have multiple risk factors, or at a serum low-density lipoprotein cholestrol level of 4.90 mmol/L (190 mg/dL) or greater for women with 0 or 1 risk factor.

5. Avoid initiating therapies to treat or prevent cardiovascular disease that have been shown to lack benefit, including antioxidant supplements and menopausal hormone therapy.

Menopause

Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291:1701-12. [PMID: 15082697] [Abstract/Free Full Text]

The first report from the Women's Health Initiative, a randomized trial of hormone replacement therapy in postmenopausal women between 50 and 79 years of age, demonstrated that the risks associated with estrogen use (including coronary heart disease, invasive breast cancer, stroke, venous thromboembolism, and dementia) outweighed the benefits (including decreased hip fracture and colon cancer) after 5.2 years (22, 23).

This arm of the Women's Health Initiative study assessed the effects of conjugated equine estrogen (CEE) alone, the most commonly used postmenopausal hormone therapy in the United States in women who have had hysterectomies. This double-blind trial involved 10 739 postmenopausal women between 50 and 79 years of age who had undergone hysterectomy. The participants were randomly assigned to receive CEE, 0.625 mg, or placebo. After an average follow-up of 6.8 years, the National Institutes of Health ended the trial early because therapy increased the risk for stroke and did not reduce the risk for coronary heart disease. The rate of stroke was increased with CEE; 158 cases of stroke were reported in the CEE group versus 118 cases in the placebo group (hazard ratio, 1.39 [CI, 1.10 to 1.77]; absolute excess risk, 12 additional strokes per 10 000 person–years). Therapy with CEE also increased the rate of deep venous thrombosis; 77 cases were reported in the CEE group versus 54 cases in the placebo group (hazard ratio, 1.47 [CI, 1.04 to 2.08]). The rate of hip fracture was decreased with CEE, with 38 fractures reported in the CEE group versus 64 in the placebo group (hazard ratio, 0.61 [CI, 0.41 to 0.91]; 6 fewer hip fractures per 10 000 person-years). The absolute excess risk for all monitored events, combined as a global index of coronary artery disease, stroke, pulmonary embolism, breast cancer, colorectal cancer, hip fractures, and death, was not significant.

On the basis of these results, CEE should be recommended only at low doses for short-term symptomatic relief, not for chronic disease prevention. This strategy is endorsed by both the U.S. Food and Drug Administration and ACOG (24, 25). The high dropout rate in this trial should be noted; by the end of the trial, 53.8% of participants had stopped taking the study medication. Consequently, both the risks and benefits of CEE were probably underestimated. Although the risks of CEE alone appear to be less than those of combined therapy with CEE and medroxyprogesterone acetate, a direct comparison of the 2 studies is not possible because of differences in study groups.

In a separate but related study of the effects of CEE therapy on incidence of probable dementia and mild cognitive impairment in women 65 years of age and older (the Women's Health Initiative Memory Study), therapy with CEE alone adversely affected cognition. The detrimental effect of CEE was greatest in women with lower cognitive function at the start of treatment. When the data from this analysis were combined with that obtained from the Women's Health Initiative study of combination therapy with CEE and medroxyprogesterone, the combined end point of dementia and mild cognitive impairment was found to be significantly increased in women receiving hormone therapy (26).

Soy Did Not Improve Cognitive Function, Bone Mineral Density, or Serum Lipid Profiles in Postmenopausal Women

Kreijkamp-Kaspers S, Kok L, Grobbee DE, et al. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: a randomized controlled trial. JAMA. 2004;292:65-74. [PMID: 15238592] [Abstract/Free Full Text]

Since the Women's Health Initiative, researchers and the lay public have become increasingly interested in alternatives to hormone therapy for the treatment of menopausal symptoms. Isoflavones are phytoestrogens, naturally occurring compounds found in soy and other plants that are known to bind to estrogen receptors (27). Soy isoflavones were initially believed to be more effective than placebo for relieving hot flashes and other perimenopausal symptoms. These findings were not confirmed in more recent studies (28).

This study investigated whether soy protein with isoflavones influenced cognitive function, bone mineral density, and serum lipid levels in postmenopausal women. In this double-blind trial, 202 healthy postmenopausal women between 60 and 75 years of age were randomly assigned to receive placebo (total milk protein powder) or 25.6 grams of soy protein containing 99 mg of isoflavones (52 mg genistein, 41 mg daidzein, 6 mg glycetein) daily for 12 months. A total of 175 women completed at least 1 postintervention analysis and were included in the modified intent-to-treat analysis. Participants generally adhered to their assigned regimens (median plasma genistein levels were 615.1 nmol/L for the soy group and 17.2 nmol/L for the placebo group).

The investigators found no statistically significant differences in cognitive function, bone mineral density, or serum lipid levels between the 2 groups after 1 year. This study did not confirm results of other studies that showed improvement in serum lipid profiles in persons taking soy supplements, possibly because most of the earlier studies were performed in men. Until the long-term effects of isoflavone use have been investigated further, physicians should not recommend soy supplementation for chronic disease prevention in postmenopausal women.

Osteoporosis

Bone HG, Hosking D, Devogelaer JP, et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350:1189-99. [PMID: 15028823] [Abstract/Free Full Text]

Bisphosphonate drugs have been shown to reduce the risk for vertebral and hip fracture in menopausal women with low bone density or preexisting osteoporotic fracture. In clinical practice, they have been continued indefinitely. However, long-term safety and efficacy data to support prolonged use have been lacking. The authors of this study reported the long-term effects of alendronate on bone density by using data from a randomized, double-blind trial comparing alendronate with placebo. In the portion of the trial reported in this paper, 247 women received active treatment with alendronate for 10 years or treatment with alendronate for 5 years followed by 5 years of placebo.

Treatment with 10 mg of alendronate daily for 10 years produced mean increases in bone mineral density of 13.7% at the lumbar spine (CI, 12.0% to 15.5%), 10.3% at the trochanter (CI, 8.1% to 12.4%), and 6.7% at the total proximal femur (CI, 4.4% to 9.1%) compared with baseline values. Smaller gains occurred in women given 5 mg of alendronate daily for 10 years. Women who discontinued alendronate after 5 years maintained a significant gain in lumbar and proximal hip bone density compared with baseline, but they had a gradual, significant loss in proximal hip bone density after discontinuing alendronate. Safety, including fracture rates and rates of gastrointestinal complications, was not statistically different between groups.

These findings suggested that alendronate is safe to use over a 10-year period, that the therapeutic effects on bone mineral density are sustained over 10 years of use, and that discontinuation results in gradual loss of bone mineral density. This study supports the current practice of continuing alendronate indefinitely in patients with osteoporosis that was diagnosed by bone densitometry or after vertebral or hip fracture. These findings, however, do not demonstrate the degree of fracture reduction with long-term alendronate use, which remains unknown.

Recurrent Vulvovaginal Candidiasis

Sobel JD, Wiesenfeld HC, Martens M, et al. Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis. N Engl J Med. 2004;351:876-83. [PMID: 15329425] [Abstract/Free Full Text]

Recurrent vulvovaginal candidiasis is defined as 4 or more symptomatic episodes of vulvovaginal candidiasis per year. Most women with recurrent vulvovaginal candidiasis have no apparent predisposing conditions. Although several medications have been shown to be effective for suppression of vulvovaginal candidiasis, a long-term cure remains elusive. Intravaginal azole therapy is effective for suppression of symptoms, but some patients consider the treatment inconvenient. Furthermore, the recommended intravaginal treatment (clotrimazole, 500 mg/wk) is not universally available. Long-term therapy with oral ketoconazole (100 mg/d for 6 months) is effective but requires regular monitoring of liver function. Oral itraconazole has also been recommended (29).

This study determined the effectiveness of long-term weekly fluconazole for the treatment of recurrent vulvovaginal candidiasis. Women were eligible for the study if they had active acute vulvovaginal candidiasis with a minimum of 4 documented episodes in the previous 12 months. Pregnant women and women with known HIV seropositivity were not eligible for the study. After treatment for acute symptoms with 3 doses of oral fluconazole, 150 mg every 72 hours, 387 women were randomly assigned to receive oral fluconazole, 150 mg weekly, or placebo for 6 months. After 6 months, 90.8% of women in the fluconazole group had no recurrence of vulvovaginal candidiasis compared with 35.9% in the placebo group (P < 0.001). The mean time to clinical recurrence in the fluconazole group was 10.2 months compared with 4.0 months in the placebo group (P < 0.001). At 12 months, 42.9% of women in the fluconazole group were symptom-free compared with 21.9% in the placebo group (P < 0.001). Results of vaginal cultures revealed no cases of fluconazole-resistant Candida albicans infection, and there was no evidence of superinfection with Candida glabrata. Fluconazole was well tolerated; therapy was discontinued in only 1 patient because of headache. Liver function tests were monitored in all patients; only 1 participant had mildly elevated serum aminotransferase levels.

In conclusion, long-term weekly fluconazole reduced the rate of recurrent vulvovaginal candidiasis and is another option for suppressive therapy. However, most patients had recurrent symptoms within 6 months of discontinuing therapy.

Acknowledgments: The authors thank their colleagues at the David Geffen School of Medicine for their assistance in preparing this article.

Potential Financial Conflicts of Interests: None disclosed.

Requests for Single Reprints: Janet P. Pregler, MD, Iris Cantor-UCLA Women's Health Center, David Geffen School of Medicine at UCLA, 100 UCLA Medical Plaza, Suite 250, Los Angeles, CA 90077; e-mail, [email protected] .

Current Author Addresses: Drs. Crandall and Pregler: Iris Cantor-UCLA Women's Health Center, David Geffen School of Medicine at UCLA, 100 UCLA Medical Plaza, Suite 250, Los Angeles, CA 90077.

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