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DOI: 10.1148/radiol.2281020298
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(Radiology 2003;228:193-199.)
© RSNA, 2003

Neuroradiology

Assessment of Brain Metastases with Dynamic Susceptibility-weighted Contrast-enhanced MR Imaging: Initial Results1

Marco Essig, MD, Michael Waschkies, MD, Frederik Wenz, MD, J. Debus, MD, PhD, H. R. Hentrich, MD and M. V. Knopp, MD

1 From the Department of Radiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany (M.E., M.W., F.W., J.D., M.V.K.), and Bracco Byk-Gulden, Konstanz, Germany (H.R.H.). Received April 9, 2002; revision requested June 5; final revision received November 5; accepted December 10. Address correspondence to M. E. (e-mail: m.essig@dkfz-heidelberg.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To assess if preradiation and early follow-up regional cerebral blood volume (CBV) measurements can help predict treatment outcome in patients with cerebral metastases and to evaluate regional CBV changes in tumor and normal tissue after radiosurgery.

MATERIALS AND METHODS: In 18 patients, dynamic susceptibility-weighted contrast material–enhanced magnetic resonance (MR) imaging was performed with a 1.5-T unit, which allowed an absolute quantification of the regional CBV. Measurements were performed prior to and at 6 weeks and 3 months after therapy. Treatment outcome was classified according to tumor volume changes at 6 months. The regional CBV of the metastases and the normal adjacent brain tissue were determined with a region-of-interest analysis. Regional CBV values were correlated with the patient outcome to assess the sensitivity and specificity of dynamic susceptibility-weighted contrast-enhanced MR imaging.

RESULTS: The pretherapeutic regional CBV was not able to help predict a treatment outcome; however, the method proved to be highly sensitive and specific for treatment outcome prediction at the 6-week follow-up. A decrease of the regional CBV value helped predict the treatment outcome with a sensitivity of more than 90%. The tumor volume change alone had a sensitivity of only 64%. The measured regional CBV values of normal brain tissue and their ratio were comparable to physiologic data and remained unchanged with therapy.

CONCLUSION: The results suggest that dynamic susceptibility-weighted contrast-enhanced MR imaging is a useful method for the assessment of radiosurgically treated brain metastases. The implemented technique with determination of the arterial input function enables an absolute quantification of the regional CBV and prediction of tumor response.

© RSNA, 2003

Index terms: Brain, blood flow, 10.38 • Brain neoplasms, metastases, 10.38 • Brain neoplasms, MR, 10.12141, 10.121411, 10.121412, 10.121416, 10.12143, 10.12144 • Brain neoplasms, therapy, 10.1299, 10.38


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Cerebral metastases are the second most common cerebral tumors in adults and occur in about 15%–25% of all cancer patients (1–2). More than 50% of all patients with intracerebral metastases have a limited number of lesions (3). For these patients, neurosurgical resection of the lesions has generally been considered the therapy of choice. However, if the lesions are close to or within functionally important brain regions, resection is not possible and patients are referred for radiation therapy (4–5). Furthermore, authors of several publications (6–10) suggest that even in resectable lesions a similar median survival can be achieved without invasive surgery with the use of stereotactic radiosurgery in which either a gamma knife or linear accelerator technique is used. The success rate of radiosurgery in brain metastases is excellent, with reported local control rates of 82%–96% (11–13).

Magnetic resonance (MR) imaging has proven to be the most sensitive diagnostic modality in the assessment of patients with cerebral metastases. Specifically, contrast material–enhanced T1-weighted MR imaging is the method of choice for lesion detection and delineation during diagnostic work-up and treatment planning (14–16). The method is sensitive enough to help rule out the possibility of multiple metastases and to permit accurate definition of the treatment target volume. After therapy, MR imaging is used for monitoring the response to treatment and for evaluation of radiation-induced side effects. Ideally, MR imaging would be able to help distinguish between local tumor recurrence, tumor necrosis, and radiation-related deficiencies of the blood-brain barrier (17–18). However, it is often unclear whether a previously reported (18–19) increase of contrast material uptake in patients with irradiated metastases is transient due to the radiation itself or is progressive due to tumor progression or necrosis. To reach a specific diagnosis and a justifiable treatment decision, additional diagnostic and clinical information is necessary (19).

Findings of previous MR imaging studies have shown that the acquisition of pathophysiologic information is achievable in patients with cerebral tumors by using functional imaging methods (20–21). In studies in patients with cerebral gliomas, it has been shown that dynamic susceptibility-weighted contrast-enhanced MR imaging in which absolute quantification of the regional cerebral blood volume (CBV) is used is able to help predict treatment outcome and monitor radiation-induced effects (22–23). As yet, however, no data are available about the role of dynamic susceptibility-weighted MR imaging in patients with cerebral metastases.

The purpose of our study was to assess if preradiation and early follow-up regional CBV measurements can help predict treatment outcome in patients with cerebral metastases and to evaluate regional CBV changes in tumor and normal tissue after radiosurgery.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The monocentric clinical trial was performed as an intraindividual follow-up study after a single high-dose radiation therapy for solitary brain metastases. The study population comprised 32 patients (age range, 29–70 years; mean age, 51.8 years): 18 women (age range, 32–70 years; mean age, 53.7 years) and 14 men (age range, 29–64 years; mean age, 48.6 years) with previously diagnosed metastatic brain lesions. All patients were referred for MR imaging of the brain for image-based radiation therapy planning. A total of three MR imaging sessions were planned for each patient: One session was conducted prior to therapy; the second, at 6 weeks after therapy; and the third, at 3 months after therapy.

The study protocol had all the appropriate approvals by the institutional review board and regulatory authorities. All patients gave their informed consent to participate in the study and had the option to withdraw at any time.

Imaging Protocol
MR imaging was performed with a 1.5-T unit (Magnetom Vision; Siemens, Erlangen, Germany) equipped with a circular polarized head coil. To guarantee identical representation of the pathologic findings in each session, the patients’ heads were immobilized in a self-developed Scotch-cast mask during each session (24). At the initial examination, the mask was closed to guarantee complete immobilization for treatment planning. The following examinations were performed with the mask opened. The imaging parameters were identical in each session and included a transverse T2- and intermediate-weighted turbo spin-echo sequence (repetition time msec/echo times msec, 4,300/93, 20; matrix, 196 x 256), a transverse T1-weighted spin-echo sequence (repetition time msec/echo time msec, 600/15; matrix, 192 x 256), localization of the arterial input function, and repetition of the T1-weighted spin-echo sequence after contrast media administration. All sequences were performed with a field of view of 230 mm and a section thickness of 5 mm. The total acquisition time in each session was approximately 45 minutes. Section orientation in all cases was parallel to the anterior commissure and posterior commissure, or AC-PC, line.

Dynamic susceptibility-weighted MR imaging was performed by using a modified simultaneous dual fast low-angle shot sequence (31/16, 25; flip angle, 10°; section thickness, 5 mm; matrix, 64 x 128) as described previously (25). This sequence enables the simultaneous acquisition of two different sections during one repetition time. One section (short echo time) was selected to cut the brain-feeding arteries perpendicularly. The second section (long echo time) was chosen to encompass representative parts of the metastasis and the surrounding normal brain tissue. Fifty-five T2*-weighted gradient-echo images were acquired before, during, and after intravenous injection of a bolus of 0.1 mmol per kilogram of body weight of gadoteridol (ProHance; Bracco Diagnostics, Princeton, NJ). The infusion rate was 5 mL/sec and started with the 10th image.

Radiation Therapy
All patients included in the study underwent single high-dose stereotactic radiation therapy. Radiosurgery was performed with 15-mV photons delivered with a linear accelerator (Primus; Siemens, Concord, Calif). Treatment planning was performed with an MR data cube with a security margin of 1 mm around the enhancing tissue. The treatment dosage varied from 15 to 20 Gy (mean, 18 Gy) for the 80% isodose.

All patients received 20 mg of dexamethasone (Fortecortin; Merck, Darmstadt, Germany) to prevent cerebral edema and 20 mg of omeprazol (Antra; Astra, Wedel, Germany) to protect the stomach mucosa before and 6 hours after radiosurgery.

Data Analysis
Images were assessed both quantitatively and qualitatively. The quantitative analysis involved determination of the regional CBV from measurements obtained at regions of interest (ROIs) placed on the tumor and the unaffected ipsi- and contralateral white matter. The ROI placed on the metastasis had a size of at least 100 pixels and included all enhancing tissue but excluded nonenhancing necrotic areas and the surrounding edema. Since normal tissue should not contain edematous changes, the ipsi- and contralateral ROIs were placed in unaffected brain areas, in areas distinct from the metastasis, with a standardized size of 100 pixels. The ROI placement was performed by a radiologist and a radiation oncologist (M.E. and F.W.) in consensus. If possible, the position of ROIs of normal tissue mirrored the affected side.

To acquire accurate regional CBV measurements, the measured time–signal intensity curves were converted first into time–concentration curves and then were fitted with a gamma-variate function to eliminate recirculation effects. Blood volume values were determined by using equations obtained from the indicator dilution theory (26) by calculating the area under the tissue time–concentration curve in approximately 20–25 ROIs per MR data set and by normalizing them to the integrated arterial input function. The arterial input function, calculated with specially self-developed interactive software, was determined as the mean time–concentration curve for pixels with characteristic attributes (a short mean transit time and a high and early concentration maximum) in the brain-feeding arteries (25,27). This allowed calculation of absolute regional CBV values.

The mean and SD of the tumor and normal tissue regional CBV were calculated at each time point of examination (initially, 6-week, and 3-month follow-up).

The qualitative analysis involved evaluation of conventional imaging data to categorize the patient’s tumor response. Tumor response to radiation therapy was classified on the basis of the 6-month follow-up findings as the following: grade 1, tumor remission (tumor volume decrease >25%); grade 2, stable disease (tumor volume decrease <25% or a tumor volume increase <25%); and grade 3, tumor progression (tumor volume increase >25%). The pretherapy tumor volume was considered the reference volume. The tumor volume was calculated by using the ellipsoid formula: {pi}/6 multiplied by the three orthogonal maximal diameters of the lesion. The qualitative categorization of the tumor response was performed independently of the quantitative analysis by another radiologist and radiation oncologist (M.W. and J.D.) in consensus.

Statistical Analysis
The tumor response was cross correlated with the regional CBV values of the tumor prior to and at 6 weeks after therapy. For the cross correlation, a {chi}2 test was used. The final tumor response was defined on the basis of the tumor volume categorization at the final follow-up of 6 months.

Sensitivity, specificity, and predictive values for treatment outcome were then calculated at the 6-week follow-up for the regional CBV and tumor volume on the basis of the tumor outcome by using the {chi}2 test. At this time point, reduction of the regional CBV or a tumor volume decrease was categorized as a tumor remission. An increase of the regional CBV or the tumor volume was categorized as a tumor progression.

The time independence (initially, 6-week, and 3-month follow-up) of the normal tissue regional CBV values was justified by using a paired Student t test.

For all statistical tests, a P value less than .05 was considered to indicate a significant difference.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Of the 32 patients included in the study, 18 (11 women, seven men; mean age, 55 years; age range, 29–69 years) completed the entire protocol. Fifteen patients had supratentorial metastasis, and three patients had infratentorial metastasis. The metastases were derived from melanoma in seven patients; renal cell carcinoma and bronchiogenic tumors in three patients each; ovarian carcinoma in two patients; and pancreatic carcinoma, cervical carcinoma, and breast carcinoma in one patient each. The patient population, treatment dose, initial tumor volume, initial regional CBV, and tumor response are summarized in Table 1.


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  		TABLE 1. Patient Data

 
Three of these patients demonstrated a pronounced tumor remission; five patients, a partial tumor remission; six patients, stable disease; and four patients, tumor progression at 6-month follow-up examination.

Tumor Regional CBV
The time course of the tumor regional CBV is summarized in Table 2. The mean initial tumor regional CBV was 9.64 mL/100 g ± 3.56 mL (SD), with a range of 4.2–15.4 mL/100 g. Only three of 18 metastases had a regional CBV lower than 5 mL/100 g. The primary tumors in these three female patients were breast carcinoma, ovarian carcinoma, and cervical carcinoma. There was no difference in initial regional CBV values between tumors that subsequently responded to therapy (responders) and tumors that did not respond (nonresponders) (P > .05, {chi}2 test). Treatment response and stable disease were indicated by a decrease in the regional CBV at both 6-week and 3-month time points. Patients with pronounced therapy response had a mean decrease of regional CBV of 25.9% (7.45–10.06 mL/100 g) at the 6-week follow-up and a mean decrease of 39% at the 3-month follow-up. In patients with a partial response, the total mean decrease in regional CBV was 33%. In patients with stable disease, the total mean decrease in regional CBV was 14%.


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  		TABLE 2. Time Course of the Tumor Regional CBV

 
In the nonresponder group, an overall increase of regional CBV values was observed. The mean regional CBV increase was 10% at the 6-week and 38.1% at the 3-month time point.

A decrease of regional CBV values was observed at follow-up in all but one of the patients with pronounced or partial response to therapy (Figs 1, 2). In two patients, a decrease in regional CBV was observed despite an overall increase of tumor volume at the 6-week time point. For these two patients, the increased tumor volume at 6 weeks after therapy was initially interpreted as a nonresponse to treatment (Fig 1). In the nonresponder group, two patients demonstrated a mild decrease of the tumor regional CBV at the 6-week time point. However, at 3 months after therapy, all patients showed a strong increase of the blood volume (Figs 3, 4).



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  		Figure 1. Patient 9. Therapy responder. MR images obtained in a 59-year-old female patient with left frontal melanoma metastasis. At 6-week follow-up, the tumor shows a 142% volume increase (arrows), while the regional CBV (rCBV) has a decrease of 85%, indicating a tumor response. Because of patient’s agitation, the head was positioned obliquely during the examination. At 3-month follow-up, the volume decreased, with only a mild increase of the regional CBV. At 6-month follow-up, the tumor volume continued to remain stable. The disease was graded as stable.

 


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  		Figure 2. Graph depicts changes in the regional CBV (rCBV) in eight patients with tumor response. Displayed are the percentages of regional CBV changes in patients with tumor response (pronounced and minor response). In all but one patient, the regional CBV decreased at 6-week and 3-month follow-up. Symbols represent individual patients.

 


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  		Figure 3. Patient 16. Therapy nonresponder. MR images obtained in a 52-year-old male patient with right occipital renal cell carcinoma metastasis. The patient had a decrease of the tumor volume at 6-week follow-up, with a subsequent tumor volume increase at 3-month follow-up (arrows). The regional CBV (rCBV) values were elevated at 6-week follow-up, indicating tumor progression.

 


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  		Figure 4. Graph depicts changes in the regional CBV (rCBV) in four patients with tumor nonresponse. Displayed are the percentages of regional CBV changes in patients with tumors that did not respond to treatment (nonresponders). At 6-week follow-up, two patients each had a decrease and an increase in the regional CBV, while at 3-month follow-up, three of four patients had an increase in the regional CBV values. Symbols represent individual patients.

 
On the basis of these observations, an early prediction of the outcome to radiation therapy was significantly (P < .02) better with the use of tumor regional CBV than it was with the use of tumor volume (Table 3). At the 6-week follow-up, the predictive values were more than 80% for the regional CBV, with a sensitivity of 91% and a specificity of 71%.


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  		TABLE 3. Sensitivity and Specificity of Treatment Outcome at the 6-week Follow-up

 
Regional CBV of Normal Brain Tissue
The regional CBV values of the normal unaffected brain tissue ipsi- and contralateral to the metastasis are summarized in Table 4. The initial and follow-up values of the normal brain tissue were substantially lower than the tumor regional CBV values, and they were within the range of previously described physiologic values. After therapy, the regional CBV values remained unchanged in both ipsi- and contralateral areas. High-precision radiosurgery did not affect the surrounding tissue owing to the steep radiation dosage decline at the border of the target volume.


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  		TABLE 4. Values of the Normal White Matter ROIs at Different Time Points

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
With an increasing number of patients with brain metastases undergoing stereotactic radiosurgery rather than resection, an imaging-based approach to patient follow-up is becoming more important. Authors of previous studies (17–19) in which MR imaging has been used have looked at typical changes in MR signal characteristics after treatment. In these studies, local treatment failures were detected on contrast-enhanced T1-weighted images as increasing contrast-enhanced volumes. However, in all three studies, a transient enlargement of the contrast-enhanced region on T1-weighted images was observed, which could not be distinguished morphologically from tumor progression. Huber and colleagues (19) reported a transient enlargement in 12% of all metastases treated with linear accelerator radiosurgery in addition to a verified treatment failure rate of 7%. Using gamma knife stereotactic radiosurgery, Peterson et al (10) found a transient enlargement in 6.4% of patients and a total failure rate of 10%. Although the transient enlargement occurred earlier (after a median interval of 3 months after therapy in the study of Huber et al) than did the progressive enlargement, authors of both studies concluded that it is impossible to clearly decide with conventional MR imaging methods to which of the two categories of treatment the patient belongs.

Since the timing of the subsequent treatment of patients with progressive contrast enhancement was difficult, additional information was considered necessary. The authors suggested that other radiologic methods such as positron emission tomography (PET) (28) or functional MR imaging methods may be helpful in making a specific diagnosis.

Authors of previous studies (29–30) in which PET with fluorodeoxyglucose was used for the assessment of patients with cerebral metastases found the method generally to be inappropriate for lesion detection because of a combination of the small size of the lesions and the accumulation of tracer in normal brain tissue. For follow-up after radiosurgery, PET was described as being superior to computed tomography and MR imaging in the differentiation between recurrence and radiation reaction and/or necrosis (31). However, temporary radiation effects were suspected of masking the remaining tumor tissue, which led the authors to suggest that repeat PET studies may sometimes be necessary. The second available follow-up study in which thallium 201–labeled chlorine single photon emission computed tomography (SPECT) and technetium 99m diethylenetriaminepentaacetic acid human serum albumin SPECT after gamma knife radiosurgery were used did not demonstrate any advantage of SPECT over MR imaging (32).

Although MR imaging has several advantages over other techniques (ie, low invasiveness, muliplanar imaging capabilities, and lack of radiation), to our knowledge, no studies have yet been published in which the use of dynamic susceptibility-weighted MR imaging for the assessment and follow-up of patients with cerebral metastases after radiosurgery was described. The use of fast MR imaging sequences and the availability of contrast agents have proven invaluable for the assessment and monitoring of physiologic and pathophysiologic cerebral processes (22,23,33–34). T2*-weighted contrast-enhanced fast imaging sequences, in particular, can be used for the assessment of tissue perfusion by applying models initially used in nuclear medicine (26). The principle underlying dynamic susceptibility-weighted MR imaging allows a low invasive assessment of regional blood volumes. In patients with low-grade astrocytomas, the method has proven effective to enable grading of the tumor and to monitor the side effects of therapy on normal adjacent brain tissue (22,23).

In the present study, we have found that the method allows an early prediction of treatment outcome in patients with cerebral metastases treated with linear accelerator radiosurgery. In 18 patients with solitary metastatic lesions, regional CBV measurements were performed prior to radiosurgery and at 6 weeks and 3 months after treatment. The follow-up interval with morphologic MR imaging was at least 6 months. The blood volume values, quantified by using an arterial input function, revealed the values for normal unaffected white matter to be comparable with previous imaging findings and physiologic data (33). An absolute quantification is crucial in this context because of the heterogeneity of metastatic brain lesions of different primary tumors. Moreover, it also enables intraindividual follow-up and subsequent interindividual crossover comparison. In metastases, the regional CBV depends on the vascularization of the primary tumor, which may explain the spread of the values in this heterogeneous group of patients. The single metastases are known to be homogeneous within the enhancing areas (2).

In the present study, differences between treatment responders and nonresponders could not be distinguished on the basis of initial tumor regional CBV values alone. Although this may be related to the pronounced spread of initial values and the limited number of patients, it may also be argued that the initial vascularization of the pathologic tissue has no influence on the radiotherapeutic effect, as was suggested previously in a study in which PET was used (34). However, on the basis of regional CBV values acquired at just 6 weeks after therapy, the treatment outcome could be predicted with a high sensitivity and specificity. In all but one patient, a decrease of the regional CBV at the first posttherapy time point indicated a treatment response. This was independent of an initial transient enlargement of the tumor, which was observed in two patients (13%). The measurement of the regional CBV was a better predictor of outcome than were morphologic features and changes of the metastases.

The findings of the present study are in agreement with previous findings in patients with cerebral gliomas. In a previous study (23), the assessment of intratumoral vascularization by means of regional CBV was used as a marker of angiogenesis in low-grade astrocytomas. These study findings have also shown the antiangiogenic effect of radiation therapy on the vascular architecture of cerebral tumors measured as a decrease in the regional CBV. By using a single high-dose treatment as in radiosurgery, the antiangiogenetic effect is extended by a direct effect on the tumor vessels. As is known from the radiosurgical treatment of cerebral arteriovenous malformations, radiosurgery induces a proliferation of the intimal layer of the vessel wall, leading to a complete obliteration even in large vessels (35). This effect may be more pronounced and arising earlier in the very small tumor vessels.

The measured regional CBV values of normal brain tissue and their ratios were comparable to data achieved with nuclear medicine techniques. Slightly higher regional CBV values in measurements with dynamic susceptibility-weighted MR imaging as compared with tracer methods may be explained by the different physical and physiologic characteristics of the techniques used. Intravasal distribution of the tracer or contrast agent may influence the measured results.

Limitations of the reported study are the limited number of patients, the use of a single-section technique, and the lack of precise outcome parameters for the regional CBV. Although there were only 18 patients who were completely assessable, all patients underwent a highly standardized imaging protocol and standardized follow-up at intervals for at least 6 months. To achieve an absolute quantification of the perfusion parameters, which is essential for follow-up studies, only the dual-section gradient-echo technique is available so far. Most of the currently used multisection techniques are based on the echo-planar imaging technique and do not allow a reliable quantification. Currently, a method in which a recently described dual-echo multisection technique (36) is used is under investigation in our department for the assessment of patients with cerebral metastases.

Because of the wide-spread initial regional CBV values, as seen in Table 1, precise outcome parameters are difficult to define. The comparison of regional CBV values with values of gray or white matter is not very promising. Outcome criteria, as proposed for the volume, were not available. On the basis of the findings of the current study, the following outcome criteria will be assessed for upcoming studies: Decrease of the regional CBV of more than 15% indicates tumor response; increase of the regional CBV of more than 15% indicates tumor nonresponse; increase or decrease of the regional CBV of less than 15% indicates inconclusive findings, which require short-term follow-up.

Despite the limited number of patients in the present study, the results suggest that dynamic susceptibility-weighted contrast-enhanced MR imaging is a useful method for the assessment of radiosurgically treated brain metastases. Pretherapeutic regional CBV values did not predict a treatment outcome of radiation therapy. A posttherapeutic decrease of regional CBV values indicated tumor response to therapy regardless of increases in tumor volume, which might be due to radiation-induced edema and blood-brain barrier disruption. The implemented technique with determination of the arterial input function enables an absolute quantification of the regional CBV, which permits prediction of tumor response.


   ACKNOWLEDGMENTS
 
The authors thank Iwan Zuna, PhD, for statistical analysis and Miles Kirchin, PhD, for review of the manuscript.


   FOOTNOTES
 
Abbreviations: CBV = cerebral blood volume, ROI = region of interest

Author contributions: Guarantor of integrity of entire study, M.E.; study concepts, M.E., H.R.H., M.V.K.; study design, M.E., M.V.K.; literature research, J.D., M.E., M.W.; clinical studies, M.E., M.W., F.W., M.V.K.; data acquisition, M.E., M.W., F.W.; data analysis/interpretation, F.W., M.W.; statistical analysis, M.V.K., F.W.; manuscript editing, M.V.K., M.E., M.W.; manuscript preparation, definition of intellectual content, revision/review, and final version approval, all authors


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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