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Indium-111–Labeled Trastuzumab Scintigraphy in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

Patrick J. Perik, Marjolijn N. Lub-De Hooge, Jourik A. Gietema, Winette T.A. van der Graaf, M. Alexander de Korte, Sharon Jonkman, Jos G.W. Kosterink, Dirk J. van Veldhuisen, Dirk T. Sleijfer, Pieter L. Jager, Elisabeth G.E. de Vries

From the Departments of Medical Oncology, Hospital Pharmacy, Nuclear Medicine and Cardiology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands.

Address reprint requests to Elisabeth G.E. de Vries, MD, PhD, Department of Medical Oncology, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, the Netherlands; e-mail: e.g.e.de.vries{at}int.umcg.nl

	ABSTRACT

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Purpose The cardiac and antineoplastic effects of trastuzumab may be related to specific uptake of trastuzumab in myocardium and tumor tissue, respectively. We evaluated whether indium-111 (¹¹¹In) –labeled trastuzumab scintigraphy can predict cardiotoxicity and identify tumor lesions. In addition, we evaluated whether plasma markers for cardiac dysfunction can be used to predict cardiotoxicity.

Patients and Methods Patients with human epidermal growth factor receptor 2 (HER2) –positive metastatic breast cancer underwent gamma camera imaging from 15 minutes to 7 days after injection of 150 MBq ¹¹¹In–diethylenetriamine penta-acetic acid anhydride (DTPA) –trastuzumab, after loading-dose trastuzumab, and after once-a-week trastuzumab doses for 11 weeks, and concomitant paclitaxel once every 3 weeks. Cardiac assessments were performed before treatment, and after four and six cycles. Plasma N-terminal probrain natriuretic peptide (NT-proBNP) and serum troponin I were measured with immunoassay.

Results Fifteen of the 17 patients were available for cardiac and tumor uptake analysis. On the first scan, myocardial ¹¹¹In-DTPA-trastuzumab uptake was observed in one patient with pre-existing cardiac arrhythmias, who did not develop heart failure during treatment. Severe cardiotoxicity occurred in three patients, without initial myocardial uptake, whereas one showed weak myocardial uptake after four cycles. The detection rate of single tumor lesions was 45%. New tumor lesions were discovered in 13 of 15 patients. Pretreatment plasma NT-proBNP levels were higher in patients with than without heart failure (mean, 534 [standard deviation, 236] v 105 [standard deviation, 79] ng/L; P = .009).

Conclusion Radiolabeled trastuzumab scintigraphy was not valuable in predicting trastuzumab-related cardiotoxicity in metastatic breast cancer patients, but can identify HER2-positive tumors. Measurement of plasma NT-proBNP is promising regarding prediction of trastuzumab-related cardiotoxicity.

	INTRODUCTION

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Tumor overexpression or amplification of the human epidermal growth factor receptor 2 (HER2, also known as erbB-2) occurs in 25% to 30% of patients with breast cancer and adversely affects their prognosis.¹ The addition of trastuzumab to chemotherapy in HER2-positive metastatic breast cancer patients resulted in an increased time to disease progression, higher objective response rates, and longer overall survival.^2,3 However, this coincided with an increased incidence of cardiac dysfunction. Recently, interim analyses of four large randomized trials evaluating trastuzumab after standard chemotherapy in HER2-positive breast cancer patients showed beneficial effects of the addition of trastuzumab to standard adjuvant treatment. These studies showed a better disease-free survival.^4-6 The combined analysis of the National Surgical Adjuvant Breast and Bowel Project B31 and North Central Cancer Treatment Group N9831 trials also showed improved overall survival. In the National Surgical Adjuvant Breast and Bowel Project B31, symptomatic heart failure had occurred at 3 years after the start of adjuvant systemic treatment in 4.1% of the patients treated with trastuzumab and paclitaxel versus in 0.8% of the patients who received paclitaxel alone. An additional 15% of the patients were taken off study for an asymptomatic decrease in left ventricular ejection fraction (LVEF).⁷ Given that trastuzumab is now entering the clinic for the adjuvant treatment of HER2-positive breast cancer patients as well, the issue of trastuzumab-related cardiotoxicity becomes increasingly relevant.

The mechanism of trastuzumab-induced cardiac toxicity is still unclear. In rodents, HER2 plays a critical role in the development of the heart. Mice deficient in erbB-2 or neuregulin, an erbB-2–activating growth factor, die early in embryonic development with severe cardiac abnormalities.⁸ Furthermore, mice with an erbB2 gene deletion restricted to the heart develop a severe dilated cardiomyopathy shortly after birth.^9,10 In addition, weak positive immunohistochemical HER2 staining was observed in myocardial biopsies from six of 60 patients with severe heart failure.¹¹ Therefore, trastuzumab may induce cardiotoxicity by specific binding to HER2 expressed in the myocardium, leading to cardiomyocyte death.

Previously, we have described the development of radiolabeled trastuzumab for clinical use and shown in a xenograft model that tumor HER2 expression can be visualized with indium-111 (¹¹¹In) –labeled trastuzumab scintigraphy.¹² Moreover, in a preliminary report, Behr et al¹³ suggested that radiolabeled trastuzumab uptake in the myocardium and tumor could predict cardiotoxicity and response to trastuzumab treatment, respectively.

The primary aim of the current study was to evaluate whether radiolabeled trastuzumab can be used for the identification of patients at risk of developing cardiac dysfunction during treatment with trastuzumab and paclitaxel. The secondary aim was to evaluate whether this technique can be used to demonstrate HER2-positive tumor localizations. In addition, we evaluated whether plasma markers for cardiac dysfunction can play a role in predicting trastuzumab-related cardiotoxicity.

	PATIENTS AND METHODS

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Patients
Eligible patients were age 18 years or older, were diagnosed with HER2-positive metastatic or locally advanced breast cancer, were suitable for treatment with paclitaxel and trastuzumab, and had an Eastern Cooperative Oncology Group performance status of 0 to 2. Before treatment, all patients underwent routine staging evaluations, which included a complete history, physical examination, and blood chemistry profile, in addition to chest radiography, computed tomography or ultrasound of the liver, and a bone scan. Tumors were considered HER2 positive if immunohistochemistry of the primary tumor showed 2/3+ membrane overexpression. Exclusion criteria were treatment with any investigational drug within 30 days before the start of the study, radiotherapy within 4 weeks of enrollment, serious uncontrolled CNS metastases, LVEF less than 40% (multigated angiogram [MUGA]), or symptomatic heart failure New York Heart Association (NYHA) functional class III or IV. In addition, patients suffering from uncontrolled serious concurrent illness, dyspnea at rest due to malignant disease, dyspnea that required oxygen therapy, or abnormal laboratory tests (defined as neutrophil count less than 1.5 x 10⁹/L, platelets less than 100 x 10⁹/L, serum total bilirubin more than 1.5x upper limit of normal [ULN], ALT or AST more than 2.5x ULN [> 5.0 x ULN in case of liver metastases], alkaline phosphatase more than 2.5x ULN [> 4.0x ULN in case of liver or bone metastases], or serum creatinine more than 1.5x ULN) were not eligible.

The study was approved by the local medical ethics committee and written informed consent was obtained from all participants. Tumor response was evaluated after two, four, and six cycles in accordance with the Response Evaluation Criteria in Solid Tumors Group criteria.¹⁴ Patients with progressive disease were taken off study.

Treatment
Patients were assigned to six once-every-3-weeks cycles of trastuzumab and paclitaxel. After the loading dose of 4 mg/kg body weight, which was administered as an intravenous infusion during 90 minutes, trastuzumab was administered as a weekly intravenous infusion of 2 mg/kg body weight in 30 minutes. Paclitaxel 175 mg/m² was administered in 4 hours as an intravenous infusion, once every 3 weeks. The first paclitaxel dose was given the day after the trastuzumab loading dose. Subsequent paclitaxel infusions were administered on the same day as the trastuzumab. Toxicity was coded according to the National Cancer Institute Common Toxicity Criteria V3.0.

Cardiac Function
Assessment of left ventricular function (history and physical examination, standard cardiac ultrasonography, and LVEF measurement by MUGA scan) was performed at baseline, after four cycles, and after completion of the treatment (Table 1). A 12-lead ECG was obtained before enrollment. Peripheral-blood samples for measurement of serum cardiac troponin I (TnI) and plasma N-terminal probrain natriuretic peptide (NT-proBNP) were collected before, and 1 and 7 days after the first trastuzumab infusion, and at the end of each cycle. Serum TnI levels were measured with a microparticle enzyme immunoassay (Abbott Axsym system; Abbott Diagnostics Division, Abbott Park, IL), with a detection limit of 0.1 g/L. Values of more than 0.5 g/L indicate myocardial injury. EDTA plasma NT-proBNP concentrations were analyzed with an electrochemiluminescence immunoassay (Roche Diagnostics, Vienna, Austria), with an ULN of 125 ng/L.¹⁵

¹¹¹In–Diethylenetriamine Penta-Acetic Acid Anhydride–Trastuzumab Scintigraphy
Trastuzumab was radiolabeled with ¹¹¹In, using diethylenetriamine penta-acetic acid anhydride (DTPA) as a chelator, as described previously.¹² The mean immunoreactive fraction is 0.87 ± standard deviation (SD) 0.06, and the radiochemical purity is more than 95%.¹² For the clinical study, a batch of trastuzumab-DTPA was produced, which was stored at –20°C. This batch was tested (efficiency of the labeling, pH, the immunoreactive fraction, sterility, and apyrogenicity) before labeling with ¹¹¹In, which was performed separately for each patient. All patients received the same product.

Radiolabeled trastuzumab scintigraphy with 100 to 150 MBq ¹¹¹In-DTPA-trastuzumab (5 mg), was performed within 24 hours after the first trastuzumab infusion and after 12 trastuzumab infusions (Table 1). Planar whole body imaging, using a two-headed gamma camera equipped with medium-energy, all-purpose collimators at a scan speed of 12 cm/min, was performed at 15 minutes, and 1, 4 to 5, and 7 days after tracer injection. Single-photon emission computed tomographic (SPECT) images of the heart region were also obtained at the above-mentioned time points, using 2 x 32 projections (two collimators x 32 projections) of 60 seconds duration.

Image and Data Analysis
SPECT reconstructions were performed with the ordered subset expectation maximization algorithm. Images were interpreted by a nuclear medicine specialist (P.L.J.) who was blinded for clinical information. Myocardial uptake was assessed visually from spot views of the cardiac region and SPECT short-axis reconstructions.

Radiolabeled trastuzumab thoracic SPECT images were fused with conventional computed tomography images (if available) to validate regions of increased trastuzumab uptake as metastatic lesions, using a LEONARDO E-soft workstation (Siemens, Erlangen, Germany)

Statistics
The statistical power of the study was based on the incidence of trastuzumab-related cardiotoxicity. Retrospective analysis of the pivotal phase III trial showed an incidence of trastuzumab-related cardiac toxicity of 27%.² As a consequence, approximately 20 assessable patients were considered to be needed to obtain cardiotoxicity in five. A sensitivity of the trastuzumab scan (fraction of patients with cardiotoxicity who have a positive scan) of at least 50% was considered to be required for the technique to be of clinical value. If none out of five patients with a significantly reduced LVEF (decrease of > 10% or a value < 40%) would have a positive scan, the sensitivity would be below 0.5 (P < .05). With an estimate that 80% of the patients who will undergo at least four cycles of trastuzumab treatment and thus have two cardiac evaluations, the estimated total number of patients needed in the study was 25.

At the time of the design of the study, trastuzumab was administered concomitantly with an anthracycline-based chemotherapy regimen. On the basis of data regarding the increased incidence of cardiotoxicity, administration of the combination of trastuzumab and anthracyclines was no longer considered safe and therefore all patients received trastuzumab with paclitaxel. In addition, shortly after opening of the study, a stopping rule was implemented. This stopping rule suggested that a sensitivity of a positive ¹¹¹In-DTPA-trastuzmab scintigraphy of 80% (P0) was required for the test to be of clinical value. Simon's two-stage optimal trial design was used as stopping rule, based on P0 = .80 and P1 = .95, with an error of .05 and a β error of .10.¹⁶ This means that the stopping rule would be activated if three patients with cardiotoxicity of the first 19 enrolled patients had a negative scan, or five of the first 42 patients had a negative scan. Quantitative variables were compared between two groups using a Mann-Whitney U test for skewed distributed variables. Paired analyses were performed with a Wilcoxon paired-samples test. Correlations between variables were calculated using Pearson's correlation coefficient test. A P value of less than .05 was considered statistically significant.

	RESULTS

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Seventeen patients entered onto the study. Patients characteristics are presented in Table 2. All patients had a HER2 3+ overexpressing primary tumor (immunohistochemistry) and had received anthracycline-containing chemotherapy before inclusion in the current study (Table 2). The median time interval between the last anthracycline treatment and the start of treatment in the current study was 11 months (range, 5 to 59 months).

Treatment was discontinued in two patients because of progressive disease. One patient with disease progression after two cycles did not undergo the second scan. The second scan was performed in 14 patients.

Cardiac Functional Assessment
Three of 15 assessable patients developed severe heart failure (Common Toxicity Criteria grade 3; NYHA functional class II to IV) after the second cycle in two patients and the fourth cycle in one patient. Table 2 summarizes the cardiac evaluation for each patient. The development of heart failure was the reason for discontinuation of trastuzumab treatment in all three patients. One of them died as a result of severe left ventricular failure and massive pulmonary embolism. Paclitaxel alone was continued for six cycles in the second patient, and no additional treatment was given in the third patient.

Pretreatment plasma NT-proBNP levels were higher in the patients with heart failure during treatment (mean, 534 [SD, 236] ng/L) than without heart failure (mean, 105 [SD, 79] ng/L; P = .009). During treatment, NT-proBNP values remained higher in these three patients.

¹¹¹In-DTPA-Trastuzumab Imaging
A total of 17 patients underwent the first radiolabeled trastuzumab scan and 14 patients also underwent the second scan.

In one of the 15 patients who were assessable for the cardiac analysis, myocardial uptake was observed on the first scan, after the trastuzumab loading dose, at 48 hours after tracer injection (Fig 1). For logistic reasons, this patient underwent imaging at 48 hours instead of 24 hours after tracer injection. She was taken off study after two cycles, with progressive liver metastases, but without symptoms of cardiac dysfunction (pretreatment LVEF, 54%). In this patient, the time interval between the last dose of anthracycline-based chemotherapy and the start of trastuzumab and paclitaxel treatment was 17 months.

View larger version (24K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Myocardial uptake in a patient with pre-existent cardiac ventricular arrhythmias. Transversal single-photon emission computed tomographic slice. () characteristic horseshoe shape of the myocardium of the left ventricle; (dotted ) liver uptake.

Three of the 14 patients developed cardiac dysfunction without myocardial uptake. This results in a 95% CI of 0% to 71% for the sensitivity of the ¹¹¹In-DTPA-trastuzumab scintigraphy for predicting cardiotoxicity. This is below the 80% that was defined in the stopping rule. As a consequence, the study was closed.

Apart from myocardial uptake, radiolabeled trastuzumab tumor uptake was evaluated. Figure 2 shows the validation of regions with increased ¹¹¹In-DTPA-trastuzumab uptake by fusion of the radiolabeled trastuzumab SPECT with computed tomography images. This was performed in four patients. Forty-five percent of all known tumor lesions detected by routine imaging techniques were detected by the scan performed shortly after the start of treatment. One or more known tumor lesions assessed with routine staging examinations were readily discernible in 14 of the 15 assessable patients. In 13 of the 15 enrolled patients, lesions not previously identified by routine staging examinations were detected on the scan performed shortly after the first trastuzumab dose. In most patients, more tumor lesions were visualized on the first scan procedure, compared with the second scan.

View larger version (88K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Fused computed tomography (CT) with indium-111–diethylenetriamine penta-acetic acid anhydride (111In-DTPA) –trastuzumab single-photon emission tomography (SPECT) image (96 hours after tracer injection). (B) CT images (top) of a patient with a large liver metastasis (). Fusion with 111In-DTPA-trastuzumab SPECT (bottom) shows correspondence of liver metastases and SPECT hot spot.

	DISCUSSION

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We hypothesized that trastuzumab-related cardiotoxicity is based on a direct effect of trastuzumab on HER2 expressed in the myocardium. In a preliminary report, Behr et al¹³ observed myocardial uptake of ¹¹¹In-labeled trastuzumab in seven of 20 patients. Six of them developed NYHA functional class II to IV heart failure, and the seventh patient had episodes of cardiac arrhythmia during trastuzumab administration. In contrast to these results, we observed myocardial uptake at the start of trastuzumab in only one patient, who had received extensive anthracycline pretreatment and had cardiac ventricular arrhythmias before trastuzumab treatment. The second scans revealed myocardial uptake in one patient who died shortly thereafter as a consequence of severe left ventricular failure. However, no myocardial uptake was observed in the three patients who developed severe symptomatic left ventricular dysfunction during trastuzumab and paclitaxel treatment. A possible explanation for this finding may be the variation in HER2 expression in the myocardium, in analogy with the variation in HER2 expression ranging from 1+ to 3+ overexpression. However, myocardial HER2, if present, is not likely to be in the same range as tumor HER2 overexpression, as was suggested by a report that showed only weak immunohistochemical HER2 expression in the myocardium in six of 60 patients with heart failure.¹¹ This lower level may be below the detection limit of the planar and SPECT imaging techniques. Alternatively, the administration of the unlabeled trastuzumab predose may also have influenced myocardial ¹¹¹In-DTPA-trastuzumab uptake. However, this is contradicted by the fact that both patients with myocardial uptake had been given full doses of trastuzumab at the time of tracer injection.

NT-proBNP and TnI measurement were included in the cardiac functional analysis, in addition to the radiolabeled trastuzumab scintigraphy, cardiac ultrasound, and MUGA scan. A remarkable finding of the current study was that median pretreatment NT-proBNP levels were above normal values and were almost five-fold higher in the patients who developed heart failure during trastuzumab treatment in comparison with the patients who did not experience symptomatic left ventricular dysfunction. This could suggest that prior anthracycline treatment induces subclinical myocardial injury and reduced compensatory reserves in these patients, which has been described previously.¹⁷ Subsequently, myocardial distress induced by trastuzumab resulted in heart failure. These findings are in line with in vitro data in doxorubicin-treated rat cardiomyocytes, in which myofibrillar disarray increases after trastuzumab.¹⁸

The issue of trastuzumab-related cardiotoxicity becomes increasingly relevant in the light of the positive effects of trastuzumab in the adjuvant setting. Tan-Chiu et al⁷ recently reported that, despite strict cardiac eligibility criteria, an increased incidence of cardiac dysfunction was observed in the trastuzumab arm, compared with the paclitaxel-alone arm. Interim analysis of a large European randomized trial showed that a decrease in LVEF of more than 10% to an absolute value less than 50% occurred in 7.1% during the first year of trastuzumab after chemotherapy, compared with 2.2% of patients not receiving trastuzumab. Heart failure occurred in 0.5% of the trastuzumab-treated patients and in none of the patients who did not receive trastuzumab.⁴ The findings of the current study suggest that plasma markers such as NT-proBNP may be of particular value for the early detection or prediction of cardiotoxicity. ¹¹¹In-DTPA-trastuzumab scintigraphy could not predict trastuzumab-related cardiotoxicity in the current population of HER2-positive metastatic breast cancer patients. However, it cannot be ruled out that this technique is of value shortly after adjuvant anthracycline treatment in breast cancer patients who subsequently receive trastuzumab in the adjuvant setting.

The secondary aim of the study was to evaluate ¹¹¹In-DTPA-trastuzumab tumor uptake. Previously unidentified lesions were visualized in 13 of the 15 assessable patients on the first scans and the overall detection rate of tumor lesions was 45% at the single-lesion level. A possible explanation for the relatively low detection rate may be the fact that on planar whole-body images, uptake intensity is dependent on tumor size, in addition to the localization of lesions. Sites closer to the body surface are more readily discernible than lesions localized deeper. Conversely, ¹¹¹In-DTPA-trastuzumab tumor uptake intensity may also be influenced by different HER2 expression levels between separate metastatic lesions within a patient. In addition, HER2 status of lymph node metastases can differ from that of the primary tumors.^19,20 In addition, recent studies indicate discordance in HER2 expression between primary tumors and asynchronous metastases or recurrences.^21,22

Based on our findings, ¹¹¹In-DTPA-trastuzumab scintigraphy may become of value for clinical practice. Given that only patients with HER2-positive breast cancer are expected to benefit from trastuzumab treatment, proper selection of patients is essential. Currently, the most widely applied techniques are immunohistochemistry and fluorescent in situ hybridization/chromogenic in situ hybridization on the primary tumor.²³ The most important disadvantages of both techniques are the need for tumor tissue and the fact that because of heterogeneity between tumor lesions, HER2 positivity (or negativity) can be missed. ¹¹¹In-DTPA-trastuzumab scintigraphy may be of value as a noninvasive technique for assessment of HER2 tumor status and for staging of HER2-positive breast cancer patients. A limitation of ¹¹¹In-DTPA-trastuzumab SPECT imaging is its spatial resolution. We currently are developing a positron emission tomography tracer. It is expected that positron emission tomography, with a higher spatial resolution than planar images and SPECT, can further improve HER2-positive tumor imaging.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Dirk J. van Veldhuisen Hoffmann-La Roche (A) Hoffmann-La Roche (B) Elisabeth G.E. de Vries Hoffmann-La Roche (B)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Patrick J. Perik, Marjolijn N. Lub-De Hooge, Jourik A. Gietema, Winette T.A. van der Graaf, Jos G.W. Kosterink, Dirk J. van Veldhuisen, Dirk T. Sleijfer, Pieter L. Jager, Elisabeth G.E. de Vries Administrative support: Patrick J. Perik, Marjolijn N. Lub-De Hooge, M. Alexander de Korte, Sharon Jonkman, Dirk J. van Veldhuisen, Pieter L. Jager, Elizabeth G.E. de Vries Provision of study materials or patients: Patrick J. Perik, Marjolijn N. Lub-De Hooge, Jourik A. Gietema, Winette T.A. van der Graaf, M. Alexander de Korte, Sharon Jonkman, Jos G.W. Kosterink, Dirk J. van Veldhuisen, Dirk T. Sleijfer, Pieter L. Jager, Elisabeth G.E. de Vries Collection and assembly of data: Patrick J. Perik, Marjolijn N. Lub-de Hooge, Jourik A. Gietema, Winette T.A. van der Graaf, M. Alexander de Korte, Sharon Jonkman, Jos G.W. Kosterink, Dirk J. van Veldhuisen, Dirk T. Sleijfer, Pieter L. Jager, Elisabeth G.E. de Vries Data analysis and interpretation: Patrick J. Perik, Marjolijn N. Lub-de Hooge, Jourik A. Gietema, Winette T.A. van der Graaf, M. Alexander de Korte, Sharon Jonkman, Jos G.W. Kosterink, Dirk T. Sleijfer, Pieter L. Jager, Elisabeth G.E. de Vries Manuscript writing: Patrick J. Perik, Marjolijn N. Lub-de Hooge, Jourik A. Gietema, Winette T.A. van der Graaf, M. Alexander de Korte, Dirk J. van Veldhuisen, Dirk T. Sleijfer, Pieter L. Jager, Elisabeth G.E. de Vries Final approval of manuscript: Patrick J. Perik, Marjolijn N. Lub-de Hooge, Jourik A. Gietema, Winette T.A. van der Graaf, M. Alexander de Korte, Sharon Jonkman, Jos G.W. Kosterink, Dirk J. van Veldhuisen, Dirk T. Sleijfer, Pieter L. Jager, Elisabeth G.E. de Vries

 

	ACKNOWLEDGMENTS

 
We thank Wim J. Sluiter for statistical support.

	NOTES

 
Supported by an unrestricted educational grant received from Hoffmann-La Roche Ltd, Basel, Switzerland.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted August 12, 2005; accepted March 6, 2006.

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