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Imaging of Adrenal Incidentalomas with PET Using ¹¹C-Metomidate and ¹⁸F-FDG

¹ Turku PET Centre, University of Turku, Turku, Finland
² Department of Oncology and Radiotherapy, Turku University Central Hospital, Turku, Finland
³ Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
⁴ Department of Internal Medicine, Helsinki University Hospital, Helsinki, Finland
⁵ Department of Internal Medicine, Turku University Central Hospital, Turku, Finland

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
Our aim was to evaluate the use of PET with ¹¹C-metomidate and ¹⁸F-FDG for the diagnosis of adrenal incidentalomas. Methods: Twenty-one patients underwent hormonal screening before dynamic imaging of the upper abdomen with ¹¹C-metomidate, and for 19 of these 21 patients, static ¹⁸F-FDG imaging followed. Uptake of ¹¹C-metomidate and ¹⁸F-FDG in incidentalomas was quantified and correlated with the hormonal work-up and the mass size on CT (median, 2.5 cm; range, 2–10 cm). Results: The final diagnoses were hormonally active adenoma (n = 7), nonsecretory adenoma (n = 5), adrenocortical carcinoma (n = 1), pheochromocytoma (n = 2), benign noncortical tumor (n = 2), normal adrenal (n = 1), and malignant noncortical tumor (n = 3). Diagnosis was established at surgery (n = 9), percutaneous biopsy (n = 4), or follow-up (n = 8). The highest uptake of ¹¹C-metomidate, expressed as standardized uptake value (SUV), was found in adrenocortical carcinoma (SUV = 28.0), followed by active adenomas (median SUV = 12.7), nonsecretory adenomas (median SUV = 12.2), and noncortical tumors (median SUV = 5.7). Patients with adenomas had significantly higher tumor–to–normal-adrenal ¹¹C-metomidate SUV ratios than did patients with noncortical tumors. ¹⁸F-FDG detected 2 of 3 noncortical malignancies but failed to detect adrenal metastases from renal cell carcinoma. All inactive and most active adenomas were difficult to detect with ¹⁸F-FDG against background activity, whereas both pheochromocytomas and adrenocortical carcinoma showed slightly increased uptake of ¹⁸F-FDG. There was no correlation between uptake of ¹¹C-metomidate or ¹⁸F-FDG and mass size. Conclusion: ¹¹C-Metomidate is a promising PET tracer to identify incidentalomas of adrenocortical origin. ¹⁸F-FDG should be reserved for patients with a moderate to high likelihood of neoplastic disease.

Key Words: adrenal gland • PET • radionuclide imaging • metomidate • ¹⁸F-FDG

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
The rate of finding unexpected adrenal masses, so-called incidentalomas, has been increasing because of increased use of CT, MRI, and ultrasound to study symptoms potentially originating from the abdomen (1). Patients with incidentalomas are subjected to hormonal screening and, sometimes, an extensive diagnostic work-up, especially if malignancy is suspected (2). Patients with a history of oncologic disease clearly have a high risk (32%–75%) for adrenal metastasis (2–4), and adrenocortical adenoma accounts for 36%–94% of incidentalomas diagnosed in patients without a history of cancer (1,2,5). Other final diagnoses for incidentalomas include pheochromocytomas, lipomas, cysts, or false adrenal masses actually arising from a nearby organ such as the liver, kidney, or stomach (1,2).

Adrenal tumors are found incidentally in up to 5% of patients, illustrating the need for an effective strategy to determine whether a patient should be treated surgically, pharmacologically, or not at all (1,2). Besides clinical history and hormonal profile, mass size and imaging characteristics play an important role in the diagnostic algorithm, which by no means has matured to a universally approved form (6). In some patients, the size, morphologic appearance, attenuation on CT, and growth pattern of the adrenal mass do not disclose its nature. A positive intracellular lipid signal on MRI suggests a benign adenoma, but in the absence of characteristic features on MRI or CT, functional imaging with radionuclides should be considered for differential diagnosis (7,8).

Recently, PET using ¹¹C-labeled metomidate was introduced for the identification of indeterminate adrenal masses (9,10). Metomidate is an inhibitor of 11ß-hydroxylase, a key enzyme in the biosynthesis of cortisol and aldosterone by the adrenal cortex. Our goal was to evaluate ¹¹C-metomidate PET in the diagnosis of incidentalomas and to study whether uptake of tracer is associated with adrenal cortex function.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
Patients
Twenty-one patients (14 female, 7 male) aged 21–79 y participated in the study. Written informed consent to undergo PET imaging was obtained from all patients, and the consent form and study protocol were approved by the Ethical Committee of the Local Hospital District. Pertinent clinical characteristics of the patients and their final diagnoses after PET are given in Table 1. The patients were referred by a certified specialist in either clinical endocrinology or oncology because of unilateral (n = 19) or bilateral (n = 2, patients 19 and 21) adrenal masses incidentally discovered during an abdominal imaging procedure (ultrasound or CT). The axial diameter of the mass was required to be at least 2 cm in one direction, and all patients with clear evidence of hormonally active tumor were excluded. Patient 7 had previously undergone a left adrenalectomy because of hormonally silent adenoma, and 6 patients had a history of malignancy without evidence of recurrence or metastatic disease.

Synthesis of Radiopharmaceuticals
¹¹C-Metomidate was prepared by a modification of the published procedure (9). ¹¹C-Methyl triflate, prepared by a standard procedure (11), was trapped at 0°C in 100 mL of acetone containing 0.5–1.0 mg of O-desmethyl precursor (R028141; Janssen Research Foundation) and 2.0–4.0 mL of freshly prepared tetrabutylammonium hydroxide (1 mol/L, aqueous). When trapping was completed, the reaction mixture was purified on a µBondapak C-18 column (125Å, 10 µm, 7.8 x 300 mm in internal diameter; Waters) using an eluent of methanol:water, 60:40, and a flow of 4 mL/min. The purified product was collected in a vessel containing 0.8 mL of sterile propylene glycol:ethanol, 7:3, evaporated, redissolved in sterile phosphate buffer (0.1 mol/L, pH 7.4), and filtered through a Gelman Acrodisc sterile filter (PN 4192, 0.2 mm; Pall Corp.). The final radiochemical yield of ¹¹C-metomidate from ¹¹C-methyl triflate was 40%–80%, with a specific radioactivity of 60 ± 20 GBq/µmol. The radiochemical purity was higher than 98% and stable for at least 2 h. Omission of propylene glycol and ethanol during evaporation decreased radiochemical purity (80%–90%), showing that the radiochemical impurities were formed by radiolysis.

The synthesis of ¹⁸F-FDG followed a previously described nucleophilic substitution procedure (12). The radiochemical purity of ¹⁸F-FDG was at least 95%, and the specific radioactivity at the end of synthesis was more than 75 GBq/µmol.

Patient Preparation
¹¹C-Metomidate and ¹⁸F-FDG PET studies were performed either on the same day or within 1 wk of each other. For both PET studies, the subjects fasted at least 6 h or overnight. Drinking of water was allowed ad libitum. Before ¹¹C-metomidate PET a 2-wk break was required from drugs that could affect uptake of tracer (ketoconazole, metyrapone). For the ¹¹C-metomidate study, 2 catheters were inserted in contralateral forearm veins to inject tracer and to draw blood samples during imaging. The blood-sampling arm was wrapped in an electric blanket to heat the arm for arterialization of blood samples. The subject was placed supine in the PET scanner with the arms held upright, and correct positioning to image the adrenals was secured with anatomic landmarks and CT images. For repositioning during the second PET study, laser lines were marked on the skin with a felt-tip pen. At least 3 h separated injection of the 2 radiopharmaceuticals, with ¹¹C-metomidate always preceding ¹⁸F-FDG. Two patients (patients 10 and 12) did not undergo ¹⁸F-FDG imaging for logistic reasons.

Image Acquisition and Processing
An 18-ring 2-dimensional whole-body PET scanner (Advance; General Electric Medical Systems) operated in 2-dimensional mode was used. The camera has bismuth germanate detectors, which image 35 planes at 4.25-mm intervals in a single session. The diameter of the field of view is 55 cm, and the axial length is 15.2 cm. Both PET studies were corrected for photon attenuation with 10- to 12-min preinjection transmission scans using robotically operated rods containing ⁶⁸Ge/⁶⁸Ga. For cases in which ¹⁸F-FDG imaging was performed in whole-body mode, 2-min postemission transmission scans were obtained.

Dynamic imaging was started by bolus intravenous injection of a median dose of 432 MBq (range, 211–444 MBq) of ¹¹C-metomidate, and a 45-min emission scan was subsequently acquired (frame rate of 5 x 60 s, 5 x 180 s, 3 x 300 s, and 1 x 600 s). Arterialized venous blood was frequently sampled for measurement of radioactivity throughout imaging and determination of metabolites of ¹¹C-metomidate. Samples for the latter were obtained at 2, 6, 10, 20, 30, and 40 min after injection of tracer. ¹⁸F-FDG imaging (n = 11) was performed in steady state starting 45 min after intravenous injection and consisted of two 10-min frames. Alternatively, whole-body scans (n = 8) were obtained in the craniocaudal direction with 6–7 bed positions, each lasting 5 min. No blood samples were taken during ¹⁸F-FDG imaging except for plasma glucose before tracer injection. The median dose of ¹⁸F-FDG was 369 MBq (range, 251–378 MBq). All image acquisition data were corrected for dead time, decay, and photon attenuation and reconstructed with an ordered-subsets expectation maximization algorithm using 4 iterations. The final in-plane spatial resolution in reconstructed images was 5 mm, and the axial resolution was 6 mm.

Blood Metabolite Analysis
Venous blood samples were collected into heparinized tubes at 2, 6, 10, 20, 30, and 40 min after injection to measure the amount of unchanged ¹¹C-metomidate and radioactive metabolites in plasma. Plasma proteins were precipitated with acetonitrile, and the supernatant obtained after centrifugation was analyzed with high-performance liquid chromatography (HPLC) using a µBondapak C-18 reversed-phase column (125Å, 10 µm, 7.8 x 300 mm in internal diameter; Waters) at a flow rate of 6.0 mL/min and a gradient of 100% acetonitrile (B) in 50 mmol of phosphoric acid per liter (A) as follows: 0 min of 75% A and 25% B, 5.5 min of 40% A and 60% B, 7.5 min of 40% A and 60% B, and 8.5–9 min of 75% A and 25% B. A LaChrom HPLC system (Hitachi/Merck) and a Radiomatic 150TR radioactivity detector (Packard) were used.

Measurement of ¹¹C-Metomidate and ¹⁸F-FDG Uptake
The adrenals were invariably seen as hot spots in the final ¹¹C-metomidate PET frame, which was used for defining regions of interest (ROI). Trace ROI function was used to outline ROIs encompassing the whole hot spot area in normal and enlarged adrenal glands, and mean (not maximum) radioactivity in the 3 consecutive axial planes with the highest radioactivity was used for further calculations. Similarly, a standard-sized circular ROI approximately 3 cm in diameter was drawn in 3 consecutive planes in the right lobe of the liver, also an organ with high uptake of ¹¹C-metomidate (10). In the kinetic analysis, the input function for uptake of ¹¹C-metomidate was corrected for 2 major labeled metabolites that constituted a variable but highly significant fraction of total plasma radioactivity. The corrected plasma and tissue time–activity curves derived from ROIs as explained above were used to calculate kinetic influx constant (K_i) values by applying the graphical analysis first described by Patlak (13). Standardized uptake values (SUVs) were also defined from the last frame, between 35 and 45 min, correcting tissue radioactivity for patient weight and injected dose (14).

Because normal adrenals have faint uptake of ¹⁸F-FDG, definition of ROIs was much more difficult on ¹⁸F-FDG PET images than on ¹¹C-metomidate PET images. Accordingly, we outlined ROIs onto ¹⁸F-FDG planes by reading ¹⁸F-FDG and ¹¹C-metomidate axial images together and by relating findings to those on corresponding CT scans. This was facilitated by the normal ¹⁸F-FDG uptake seen in liver, spleen, kidneys, and, variably, in stomach and bowel. The second of the 2 time frames (55–65 min) was used for calculation of SUV in adrenals and liver, again using the mean value over 3 consecutive planes. For whole-body ¹⁸F-FDG studies, only one 5-min frame was available for SUV calculation.

Statistical Analysis
Commercially obtained software (SPSS, release 11.0.1, standard version; SPSS Inc.) for Windows (Microsoft) was used for statistical evaluation. Results are expressed mostly as median and range. Normality of quantitative data was assessed with the Kolmogorov–Smirnov test. For normally distributed data, ANOVA and the independent-samples t test was used; for other data, nonparametric methods (the Kruskal–Wallis test and Mann–Whitney U test) were applied. The association between K_i and SUV was evaluated with the Pearson correlation coefficient. All P values are 2 tailed.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
Final Diagnosis of Incidentalomas
The final diagnoses of 21 patients included 7 active adenomas as evidenced by a deficient dexamethasone suppression test, 5 inactive adenomas, 1 adrenocortical carcinoma, 2 pheochromocytomas, 1 cyst, 1 lipoma, 1 normal adrenal falsely interpreted as tumor, and 3 noncortical malignancies (Table 1). Of the patients with active adenomas, 3 of 7 (43%) underwent adrenalectomy, whereas operation was withheld from the remaining 4 because of intercurrent disease (n = 3) or unexpected death due to coronary artery disease (n = 1). Diagnosis was confirmed histologically or cytologically for 13 patients and, for the remaining 8 patients, by characteristic radiologic appearance combined with concordant hormonal blood test findings and follow-up lasting a median of 14 mo (range, 9–21 mo). Patient 20 had well-differentiated hepatocellular carcinoma presenting as a pseudoadrenal mass (1).

Quantification of ¹¹C-Metomidate Uptake
Identification of adrenocortical adenomas and normal adrenal glands was easy with ¹¹C-metomidate PET because of the invariably high uptake of tracer in target organs with functional steroid hormone synthesis. In accordance with Bergström et al. (10), liver and, more variably, stomach and duodenum also showed moderate to high ¹¹C-metomidate uptake, which did not interfere with radioactivity seen in adrenal tissues in late images. PET images of 4 patients with different types of adrenal incidentalomas are shown in Figure 1.

View larger version (96K): [in this window] [in a new window]   FIGURE 1. 11C-Metomidate (left column) and 18F-FDG (right column) PET images of patients with adrenal incidentalomas: a left-sided hormonally inactive adenoma (patient 11) (A and B), a right-sided cortisol-secreting adenoma (patient 2) (C and D), a right-sided adrenocortical carcinoma (patient 13) (E and F), and a right-sided hepatocellular carcinoma described as "pseudoadrenal mass" (patient 20) (G and H). The images are coronal sections through the midabdomen obtained between 25 and 45 min (11C-metomidate) or 45 and 65 min (18F-FDG) after injection. Tumor is indicated in each case by a white arrow, and normal adrenal, when visible in the same section, by a black arrow. All adrenocortical tumors (first 3 rows) have much higher uptake of 11C-metomidate than of 18F-FDG, whereas the opposite is true for the noncortical neoplasia shown in the lowest row. In this case (G), uptake of 11C-metomidate is not confined to tumor but occurs in a rim of adrenal tissue (black arrow) displaced by the mass. Initially, the high 18F-FDG uptake of the adenoma in 1 d was misjudged as metastasis, with an average SUV of 3.9 (maximum, 6). Liver has invariably high uptake of 11C-metomidate, and tracer excreted in the urinary tract presents the highest radioactivity in 18F-FDG images.

View larger version (13K): [in this window] [in a new window]   FIGURE 2. Representative HPLC chromatogram of a venous plasma sample at 6 min after tracer injection showing 3 peaks designated as metabolites 1 and 2 and native 11C-metomidate (MTO). The retention times for peaks 1, 2, and 3 are 2.3, 3.2, and 6.6 min, respectively.

View larger version (17K): [in this window] [in a new window]   FIGURE 3. Time–activity curve for venous plasma and selected tissues (A) and Patlak graphical analysis for adenoma, normal adrenal, and liver (B) in a patient undergoing dynamic 11C-metomidate PET. The high contribution of blood metabolites of 11C-metomidate in the uncorrected plasma curve make it inappropriate for graphical analysis.

View larger version (17K): [in this window] [in a new window]   FIGURE 4. Average 11C-metomidate SUV in incidentaloma. Dotted lines show variability within 12 normal adrenals, excluding a single exceptionally low value of 4.6. The SUV in lipoma was relatively high, most likely because of the contribution of normally functioning adrenal tissue.

Comparison of ¹¹C-Metomidate and ¹⁸F-FDG
¹⁸F-FDG was not helpful in distinguishing adrenal tumors, with the exception of 2 of the 3 noncortical malignancies, which had characteristically high glycolytic activity coupled with low uptake of ¹¹C-metomidate (Figs. 1G and 1H). Of interest was the relatively low uptake of ¹⁸F-FDG in adrenocortical carcinoma (average SUV = 2.9 and maximum SUV = 3.8; Fig. 1F) and in bilateral adrenal metastases from renal cell cancer, which had low maximum SUVs of 2.4 and 2.3. The primary tumor in the right kidney had been previously embolized and was difficult to see in the vicinity of high ¹⁸F-FDG activity excreted in the pelvis. Although ¹⁸F-FDG was believed to generally be less informative than ¹¹C-metomidate, active adenomas (median SUV = 2.3; range, 1.8–3.9; n = 7) and the 2 pheochromocytomas (average SUVs = 3.0 and 2.9) showed higher uptake of ¹⁸F-FDG than did the 3 inactive adenomas, with SUVs of 1.6, 1.7, and 1.7 (Figs. 1B and 1D). Again, no association between tracer uptake and mass size could be found.

To assess the relationship between adenoma metabolism and hormonal activity, ratios of tumor to normal adrenal were defined for ¹¹C-metomidate and ratios of tumor to liver, for ¹⁸F-FDG. The ¹¹C-metomidate ratio could distinguish both active and inactive adrenocortical adenomas from other tumors (active vs. others, P = 0.003; inactive vs. others, P = 0.019) but was not different between hormonally active and inactive adenomas (Fig. 5). The ¹⁸F-FDG ratio in noncortical tumors (n = 7) was not different from that in any other adrenal masses, including active and inactive adenomas (n = 12). This lack of significance depended strongly on the low number of malignant lesions and unexpectedly low uptake of ¹⁸F-FDG in 2 of these 4 neoplasias.

View larger version (12K): [in this window] [in a new window]   FIGURE 5. Box plots of SUV ratios for patients with active and inactive adenomas and noncortical tumors: tumor to normal adrenal for 11C-metomidate (MTO) (A) and tumor to liver for 18F-FDG (B). The error bars and lines within boxes represent the highest and lowest quartiles and the medians, respectively, of the data distribution. The 11C-metomidate SUV ratio well distinguishes adenomas from other tumors, whereas 18F-FDG shows clearly higher values for noncortical tumors. Because noncortical tumors have a very mixed character, they do not take up significantly more 18F-FDG than do adenomas.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

The current study was performed under European COST action B12, aiming to develop a noninvasive test for evaluation of adrenal incidentalomas with PET. We looked specifically at the uptake kinetics of ¹¹C-metomidate in tumors and normal adrenal glands and in liver and venous plasma and compared the findings with those on ¹⁸F-FDG images obtained in steady state. In line with the preclinical validation study (9) and the first clinical study (10), we could demonstrate high uptake of ¹¹C-metomidate in adrenocortical tumors and normal adrenal glands as a sign of sustained 11ß-hydroxylase activity. Decreased tracer uptake, in comparison with physiologic uptake, was seen in pheochromocytomas, cysts, and noncortical malignancies such as lymphoma and metastatic carcinomas, whereas adrenocortical carcinoma had the highest uptake of ¹¹C-metomidate among all lesions. ¹⁸F-FDG was clearly inferior to ¹¹C-metomidate for depicting adrenal lesions if they were adenomas and, somewhat surprisingly, also in the solitary case of adrenocortical carcinoma. The low uptake of ¹⁸F-FDG in adrenal metastases from renal cell cancer was less surprising because ¹⁸F-FDG is known to have only a limited role in the diagnosis of renal cell carcinoma (18).

The uptake kinetics of ¹¹C-metomidate in adrenal tissue are favorable for PET imaging because irreversible binding of the tracer occurs over the first 45 min (Fig. 3). Because 2 large fractions of ¹¹C-metomidate metabolites occur in plasma, it is necessary to correct the plasma input function for these yet unidentified radiochemical species before applying graphical analysis to assess binding of ¹¹C-metomidate. This correction was successfully performed for 12 patients to calculate graphical influx constant K_i (Fig. 3), and in further analysis we showed that the obtained K_is could be replaced by the robust SUV approach commonly used in clinical oncology (4,14). K_i and SUV were not associated with mass size, and pheochromocytomas were seen to have the highest uptake in the outer rather than the inner zone of tumor—a finding compatible with the steroid-synthesizing property’s being the major determinant of uptake of ¹¹C-metomidate in adrenal tissue (9). This does not translate, however, to a direct measure of rate of adrenocortical hormone synthesis, since the SUVs in active and inactive adenomas overlapped widely, in keeping with the findings of Bergström et al. (10). Furthermore, uptake ratios for adenoma to contralateral adrenal gland were not significantly different between active and nonsecretory adenomas (Fig. 5).

Although ¹¹C-metomidate PET does not immediately replace ¹³¹I-labeled cholesterol derivatives in the functional evaluation of adrenal cortex, a search for new tracers applicable to positron imaging is in order with the widespread expansion of dedicated PET scanners. The major advantages of PET are rapid completion of the imaging, within 1 h, and a resolution and sensitivity better than those of adrenal scintigraphy. Clearly, the value of quantitative ¹¹C-metomidate PET will remain obscure until the results from the larger European multicenter study are at hand. In our trial, most patients were seen by a clinical endocrinologist; we hope that on that basis the multicenter trial included more patients with metastatic tumors and thus avoided the slight referral bias of the current study. Unfortunately, it seems difficult to distinguish adrenocortical adenoma from carcinoma with the current technique, but for a patient with known carcinoma, ¹¹C-metomidate should be a specific tracer for metastatic disease (10). For patients presenting with adrenal masses and a history or strong suggestion of neoplastic disease, ¹⁸F-FDG PET may still be the study of choice because whole-body imaging may conceal other deposits of cancer in addition to adrenal metastasis (15).

	CONCLUSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
We conclude that the pattern of ¹¹C-metomidate uptake facilitates discrimination between various types of adrenal masses, suggesting that ¹¹C-metomidate PET may be useful for functional evaluation of incidentalomas. The radiologic features of the adrenal mass, a clinical history addressing the risk for malignant disease, and the hormonal profile of the patient should be considered when assessing the advantages of ¹¹C-metomidate relative to those of other positron-emitting tracers such as ¹⁸F-FDG and scintigraphic techniques using cholesterol derivatives or ¹²³I-metaiodobenzylguanidine. Further to be emphasized is that ¹¹C-metomidate PET, rather than representing a new modality to replace the established methods, remains complementary to CT and MRI in the diagnosis and management of incidentalomas.

	ACKNOWLEDGMENTS

 
We are grateful to Professors Bengt Långström and Mats Bergström from Uppsala PET Centre, Sweden, for sharing their expertise in ¹¹C-metomidate imaging. The staffs of the Turku Cyclotron and the Radiochemistry Laboratory are thanked for technical support and advice, and the technologists at the PET Centre are thanked for excellent help in imaging the patients. This work was supported in part by European Union COST action B12 (http://cost.cordis.lu).

	FOOTNOTES

 
Received Oct. 20, 2003; revision accepted Dec. 29, 2003.

For correspondence or reprints contact: Heikki Minn, MD, Department of Oncology and Radiotherapy, Turku University Central Hospital, P.O. Box 52, FIN-20521 Turku, Finland.

E-mail: heikki.minn{at}utu.fi

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 

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