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2009 THE AUTHORS. JOURNAL COMPILATION Mini Reviews 2009 BJU INTERNATIONAL MRSI IN THE MANAGEMENT OF PROSTATE CANCER NAYYAR et al. BJUI Magnetic resonance spectroscopic imaging: current status in the management of prostate cancer BJU INTERNATIONAL Rishi Nayyar, Rajeev Kumar, Virendra Kumar*, Naranamangalam R. Jagannathan*, Narmada P. Gupta and Ashok K. Hemal Departments of Urology and *NMR, All India Institute of Medical Sciences, New Delhi, India Accepted for publication 17 December 2008 In the past decade several advances have been made in the field of nuclear magnetic resonance (NMR) imaging. MR spectroscopic imaging (MRSI) is one such advance which holds promise for detecting biochemical change on imaging of the prostate, and that INTRODUCTION Prostate cancer is common and remains the second leading cause of cancer death among elderly men. Current methods for its detection, i.e. a DRE, TRUS, PSA assay and even sextant biopsy have limited accuracy for most early prostate cancers. This challenge in diagnosis, localization and staging of potentially curable early disease has prompted further research into radiological imaging which could be more specific and sensitive, and that provides good positive/ negative predictive value (PPV/NPV). MRI is well known for its diagnostic potential, primarily due to its capability to noninvasively generate high-resolution anatomical images based on various inherent tissue characteristics. With ongoing research on ways of data acquisition during MRI and their analysis, newer sequences and strategies have been developed that provide more specific information (diffusion imaging, functional imaging, metabolic imaging, etc.), faster image generation and higher resolution. With these newer technologies, the diagnostic potential of MR techniques is improving further, and its indications are also developing. MR spectroscopic imaging (MRSI) is one of these new promising techniques, and uses the regular MRI machine, requiring only software upgrades as an additional cost factor. 1614 can be used in several ways for improving the management of patients with prostate cancer. We review the literature, technique and basics of MRSI, with its current status in various situations as applied to the management of prostate cancer. KEYWORDS MRSI: PRINCIPLES, DATA ACQUISITION AND BASIS FOR DIAGNOSIS OF PROSTATE CANCER metabolites or biochemical species that are at low concentration. The detailed description of MRI/MRSI is outside the purview of this clinical article and interested readers are referred to radiological textbooks and other review articles [1]. Only the salient features are highlighted here. All MR techniques are based on the phenomenon of nuclear magnetic resonance (NMR). In vivo MRS of organs and tissues is an extension of highresolution NMR spectroscopy and is based on the resonance of protons in the nuclei of different chemical constituents of the tissue. When placed in a homogenous magnetic field, the different protons present in a molecule do not experience the same magnetic field depending upon the amount of shielding of the nucleus inherent in the molecular structure, and therefore resonate differently. The main difference between MRI and MRS is that in MRI the signal is acquired in the presence of magnetic-field gradients, while for MRS it is necessary to have a homogenous magnetic field to observe the chemical shift differences of metabolites and therefore, no magnetic field gradient is applied during signal acquisition. In MRI, signals originating from protons (1H) present in water and fat are recorded to generate images, while the purpose of MRS is to detect signals from 1H present in other BIOCHEMICAL BASIS FOR DIAGNOSIS OF PROSTATE CANCER ON MRSI magnetic resonance spectroscopy, prostate cancer imaging, prostate cancer The prostate gland has the unique feature of producing extraordinarily high levels of citrate from the epithelial cells of peripheral zone (PZ) [2]. This occurs due to a limiting activity of the enzyme ‘aconitase’ which converts citrate to isocitrate, in the first step of the Krebs cycle. This enzyme is inhibited by the presence of high levels of mitochondrial zinc, which is another unique feature of the prostate (Fig. 1). Normal prostate and BPH tissue contain citrate levels of 8000–15 000 nmol/g while all other tissues contain 150–450 nmol/g. However, in prostate cancer the levels of zinc are low and the tissue citrate levels are decreased to 1000–2000 nmol/g. In contrast to citrate, choline levels increase in prostate cancer due to changes in cell membrane synthesis and degradation that occurs with the development of human cancers [3]. These metabolic changes in prostate tissue might occur before morphological changes in tissues [4] and theoretically might be of value in detecting latent, unsuspected prostate cancer where routine histological sections have failed to detect malignancy. © JOURNAL COMPILATION © 2009 THE AUTHORS 2 0 0 9 B J U I N T E R N A T I O N A L | 1 0 3 , 1 6 1 4 – 1 6 2 0 | doi:10.1111/j.1464-410X.2009.08446.x MRSI IN THE MANAGEMENT OF PROSTATE CANCER FIG. 1. The citrate synthesis pathway in normal prostate epithelial cells. High levels of intramitochondrial zinc inhibit aconitase activity, which limits the conversion of citrate to isocitrate. This results into net citrate production by the prostate. FIG. 2. (A) A spectrum from one voxel; (B) a spectral map; and (C) a metabolite-ratio map of the prostate in a patient with a PSA level of 8.9 ng/mL. a Glucose Basilar surface Cit Cell membrane Pyruvate 0.2 Acetyl CoA 0.1 Mitochondria Cr Citrate Oxaloacetate Aconitase TCA Cycle Malate Cho Zn++ 0.0 4 3 2 ppm 1 Isocitrate b Succinate α-Ketoglutarate Cytoplasm Acinar lumen Citrate c MRSI DATA ACQUISITION AND CRITERIA TO DIAGNOSE PROSTATE CANCER MRS is based on the detection of different metabolites that have characteristic resonant frequency (primarily determined by the chemical structure). In vitro MRS refers to MRS of extracts of tissues, while in vivo MRS refers to obtaining a spectrum from an anatomically defined region noninvasively. Some widely used localization schemes [1] used for in vivo MRS are: (i) Surface-coil localization; (ii) depth-resolved surface-coil spectroscopy; (iii) single-voxel spectroscopy; and (iv) spectroscopic imaging. MRSI (also called multivoxel spectroscopy or chemical shift imaging) is a method for collecting spectroscopic data from multiple voxels covering a large volume of interest in a single measurement. It allows the acquisition of spectra from smaller voxels than single-voxel techniques. After acquisition of data, it can be examined as single spectra, a spectral map or metabolite images (Fig. 2). Both spectral maps and metabolite images can be overlaid on the MR image. © The MRSI data can be obtained within the same examination as the endorectal MRI. All data are acquired using a scanner system which consists of a solenoid, superconducting magnet that produces a strong and highly homogeneous magnetic field (B0) across the imaging volume (Fig. 3a). Gradient coils, shim coils and radiofrequency (RF) coils are also placed inside the magnet. Gradient coils produce additional linear electromagnetic fields to systematically vary B0 in any direction. Shim coils are used to compensate for B0 inhomogeneities. RF coils generate a B1 field used to excite the spins, and to detect the signals originating from the sample. The RF coil permanently installed in the MR system is the body coil. RF coils are relatively simple circuits and can be changed in design depending on the application. Dedicated surface coils, with geometry optimized for specific body parts, can be used to receive the RF signal with greater sensitivity. The use of the endorectal surface coil has made possible three-dimensional (3D) MRSI of prostate with better sensitivity (Fig. 3b). MRI with a body coil (Fig. 3c) lacks sufficient resolution to show fine anatomical details of the prostate and periprostatic tissues [5]. Currently, the resolution of MRSI with machines of 1.5 T is a voxel size of ≈0.3 cm3. However, better resolution is possible with 3 T, and is <0.2 cm3. An endorectal coil is inserted using lignocaine jelly. The total 3D MRSI examination time, including patient positioning, coil placement, imaging and spectroscopy, is ≈1 h. Then localizer images are acquired on a ‘True fast imaging with steady state precession’ sequence and the correct position of the endorectal coil is checked. These sagittal images are used to plan T2-weighted sagittal images, which in turn are used to plan T2weighted coronal images. Finally, T2-weighted transverse images are planned on coronal and 2009 THE AUTHORS JOURNAL COMPILATION © 2009 BJU INTERNATIONAL 1615 N AY YA R ET AL. FIG. 3. (a) 1.5 T whole-body MR scanner, showing the position of the patient in the scanner and the direction of magnetic field; (b) an endorectal coil; and (c) a body-flex array coil. TABLE 1 Metabolite ratio from various MRS studies to differentiate between benign and malignant prostate tissue Reference [7] [8] [9] [10] [11] [12] Method SVS MRSI MRSI MRSI SVS MRSI Metabolite ratio citrate/choline + creatinine choline + creatinine/citrate choline + creatinine/citrate choline + creatinine/citrate citrate/choline + creatinine choline + creatinine/citrate Mean (SD) metabolite ratio for PZ Normal Cancer 1.28 (0.14) 0.67 (0.17) 0.54 (0.11) 2.1 (1.3) (>0.86) – 2.1 (1.3) 0.22 (0.13) 1.62 (2.08) 2.16 (0.56) 0.31 (0.25) – >0.68 BPH 1.21 (0.29) – – – 1.43 (0.58) – SVS, single-voxel spectroscopy. MRSI at our centre are: TR 1300 or 650 ms, TE 120 ms, voxel size 5 × 5 × 5 mm3, average 3, with a total acquisition time of 17 min. All spectroscopic data processing is then carried out using pre-loaded software. The spectrum from individual voxels is Fourier-transformed, frequency aligned, phased, and if needed, baseline corrected [6]. sagittal images, keeping transverse images perpendicular to the craniocaudal axis of the prostate. Images are then acquired covering the entire prostate using a turbo spin echo sequence, with a repetition time (TR) of 2200–5000 ms, an echo time (TE) of 98 ms, field of view of 280, a matrix size 256 × 256 and a slice thickness of 5 mm, with no interslice gap. For MRSI, a point-resolved spectroscopy localized 3D-MRSI sequence is used. A ‘MEGA’ pulse is used for simultaneous suppression of lipid and water. The suppression of signals from peri-prostatic fatty tissue is similarly essential, as it can produce false-positive results. Six to eight outer-volume saturation bands are used to suppress the signal originating from periprostatic fatty tissue. Manual shimming can be used to achieve a line width of <24 Hz (full width at half maximum). An MRSI matrix with scan resolution of 16 × 16 × 8 (interpolated to 16 × 16 × 16) is used in the weighted acquisition mode, optimizing the signal-to-noise ratio (SNR) obtained per unit measurement time. The parameters used for 1616 To calculate the metabolite ratio [citrate/ (choline + creatinine)], the area under each peak of the spectrum is determined on the basis of resonance position and peak widths. On MRSI, choline, creatine and citrate have distinctive peaks resonating at 3.2, 3.0 and 2.6 ppm, respectively (Fig. 2a). The metabolite ratio is calculated from peak integral values determined for each peak. Creatinine is added to choline because the spectrum of creatinine lies very close to choline and clinically sometimes it might not be possible to differentiate between the spectra. The values of the metabolite ratio in normal PZ, cancer and BPH tissue, as given in a few reports, are shown in Table 1 [7–12]. Polyamine is another new metabolite whose peak can now be resolved at 3.1 ppm with the newer spectroscopic sequences and MRI machines of higher magnetic field strength [13]. Unlike choline, this polyamine peak decreases in the presence of prostate cancer. Shukla-Dave et al. [14] recently reported a statistically based classification rule for identifying voxels containing cancer based on both the (choline + creatine)/citrate ratio and the polyamine peak. FACTORS INFLUENCING THE RESULT OF MRSI Standardization of the technique of data acquisition and interpretation is mandatory for MRSI, as it is not widely practised. The size and shape of the endorectal/surface coils, the alignment of the coil with respect to the prostate, distance of the voxel from the receptor coils, the size of the voxels, volumeaveraging effect, SNR, mixing of signals from the nearby tissues like seminal vesicles (that have high choline levels), lipid contamination, the definition of a threshold ratio for malignancy, movement of the patient during data acquisition, etc., are some factors that might directly influence the outcome of MRSI in any patient. MRSI should therefore be interpreted considering all the possible misleading factors. STATUS OF MRI/MRSI FOR THE CLINICAL DIAGNOSIS OF PROSTATE CANCER On MRI, prostate cancer is usually seen as a low signal-intensity lesion in a hyperintense PZ on a T2-weighted image. This is due to increased cell density and a loss of the prostatic ducts compared to the healthy tissue. MRI alone has relatively poor specificity, with false-positives resulting from other conditions like biopsy artefacts, fibrosis, prostatitis, hyperplastic nodules and posttreatment changes which also appear hypointense. The combined use of endorectal and phased-array coils allows improved accuracy of MRI up to 75–90% [15], and a sensitivity and specificity of 61–77% and 46–81%, respectively [16]. MRSI differentiates between benign and malignant tissue based on metabolic changes (Fig. 4). A (choline + creatinine)/citrate ratio of >0.86 or citrate/(choline + creatinine) of <1.4 was found to be a very specific marker for prostate cancer, with 98% of the cancer ratios falling above three SDs of the mean healthy PZ value [8]. However, despite the initial enthusiasm it has not been able to replace the © JOURNAL COMPILATION © 2009 THE AUTHORS 2009 BJU INTERNATIONAL MRSI IN THE MANAGEMENT OF PROSTATE CANCER FIG. 4. Representative 3D MRSI spectra obtained from the PZ of the prostate from (a), a normal volunteer (aged 28 years), (b) a patient with BPH, and (c) a patient with malignancy in the PZ. a b Cit Cit was high and approaching 100%. Even on following the patients for >2 years the high NPV of MRSI was maintained [22]. This fact might help in selecting cases where TRUSguided biopsy might not be required even in presence of a raised PSA level. 0.3 STATUS FOR LOCATING PROSTATE CANCER AND IMPROVING CANCER DETECTION RATES ON BIOPSY 0.2 0.2 0.0 4 Cr Cho Cr 0.1 Cho 0.1 3 2 ppm 1 0.0 4 3 2 ppm 1 Cho c 0.08 0.06 0.04 Cit Cr 0.02 0.00 4 3 2 ppm 1 biopsy as a clinical means to diagnose prostate cancer. False-positive results could arise from signal contamination from the seminal vesicles, assigning a noise level to undetectable peaks to calculate a metabolite ratio, chronic prostatitis, high-grade prostatic intraepithelial neoplasia, previous biopsy, small gland, etc. False-negative results could arise from the volume-averaging effect (signal from a small malignant focus being averaged out with the signals from the surrounding benign tissue), failure to take a biopsy exactly from the malignant voxel on MRSI, tumour in the transition zone (TZ), etc. Moreover, the differentiation of benign vs malignant tissue is presently limited to the PZ only. Even though metabolites can be evaluated throughout the gland [17,18], there are no established criteria for identifying ‘cancerous’ voxels on MRSI in the TZ. Due to stromal BPH, glandular BPH and chronic prostatitis, the choline- and citratebased ratios overlap considerably between the benign and malignant groups in the central/ © TZ. Further, there are variations in metabolite levels near the ejaculatory duct. Considered alone, 3D MRSI has higher specificity for identifying cancer than MRI. However, they can be combined to improve the ability to identify cancer within the prostate. Scheidler et al. [16] showed that high specificity (91%) was obtained when combined MRI/3D MRSI indicated cancer, whereas a high sensitivity (95%) was obtained when either test provided a positive result. Comparison of MRI/3D MRSI data with stepsection histology of the prostate has shown a higher sensitivity, specificity and PPV than standard sextant biopsy of the prostate [19,20]. Our studies on this subject have shown the sensitivity, specificity, positive and NPV to be 98%, 40%, 43% and 97%, respectively, for MRSI in the diagnosis of prostate cancer [21]. Even though the PPV remains poor, the NPV TRUS biopsies are limited by a low sensitivity of 60%, a PPV of only 25% and false-negative rate estimated to be as high as 15–34% [23,24]. Combining MRSI with TRUS-guided biopsy could help in (i) directing biopsy to the suspicious area and therefore improve its detection rate, and (ii) avoiding the biopsy in those who have no suspicious lesions and therefore avoiding all risks associated with an invasive biopsy. 3D MRSI data can be overlaid on corresponding T2-weighted MRI images to identify the anatomical and pathological location of spectroscopic voxels. Tri-planar coordinates of the suspicious area can thus be obtained and used to take a biopsy from the suspicious area under TRUS guidance [25]. The addition of MRSI to MRI has been shown to improve the localization of cancer to a sextant of the prostate, with a sensitivity of up to 95% and a specificity of 91% when compared with MRI alone (P < 0.05) [16,26]. We prospectively evaluated the role of MRI/MRSI in men with a PSA level of <10 ng/mL, who have poorest cancer detection rate and the highest false-negative rate on TRUS biopsy, and found a cancer detection rate about three times better, and a NPV approaching 100% [21,25]. The TRUS biopsy probe is obliquely directed on to the prostate while the voxels on MRI/MRSI are in the vertical or horizontal planes. This might make it difficult to exactly overlay the coordinates obtained from the MRI on to the image during TRUS. Therefore MRIcompatible biopsy systems have been developed that can help to guide the biopsy, thereby totally avoiding TRUS [27]. STATUS FOR FOLLOW-UP OF PATIENTS WITH RAISED PSA LEVELS AND SELECTION FOR REPEAT BIOPSY Besides biochemical imaging with a high NPV, 3D MRSI also makes the analysis of the 2009 THE AUTHORS JOURNAL COMPILATION © 2009 BJU INTERNATIONAL 1617 N AY YA R ET AL. entire prostate gland in vivo possible. This is unlike the needle-core biopsy, which analyses only a small fraction of prostatic tissue. Thus, MRSI can be used as an additional measure to exclude carcinoma in a patient who has a raised PSA level but a benign biopsy report. This might help in selecting cases for a repeat biopsy, thereby avoiding risks of repeated saturation core biopsies in those with no suspicious voxels, and improving the detection rate of those who undergo repeat biopsy by directing biopsies to suspicious areas [28,29]. We have shown that MRSI-negative cases with a PSA level of <10 ng/mL and one negative biopsy report can be safely followed with PSA levels alone [22]. STATUS FOR TUMOUR GRADING AND TUMOUR VOLUME MEASUREMENT FOR DIFFERENTIATING BETWEEN CLINICALLY SIGNIFICANT AND INSIGNIFICANT CANCERS Choline increases and citrate reduction have been reported to be related to the aggressiveness of prostate cancer and Gleason grade. The choline concentration was the most significant predictor of Gleason score, being significantly (P < 0.001) higher in high-grade (Gleason >7) than moderate grade (Gleason <7) cancers [30,31]. Due to considerable heterogeneity of prostate cancers and biopsy sampling errors, cancers are often not detected or inaccurately graded on biopsy. In these cases 3D MRSI might help in correct grading by analysing the entire gland noninvasively, and thus providing a better preoperative prediction of Gleason grade. This information can be important in cases where the choice of treatment is critically dependent on Gleason grade. In these cases, further confirmation of the highest grade of the tumour might be obtained by directing the biopsy to the area suspected of harbouring the highest grade of cancer on MRSI. Although adding 3D MRSI to MRI has been shown to increase the overall accuracy of measuring the prostate tumour volume, the variability in measurement limits the consistent quantitative tumour volume estimation, particularly for small tumours [26]. Therefore, the role of MRSI/MRI in differentiating significant and insignificant tumours based on tumour volume remains uncertain. 1618 STATUS FOR STAGING OF PROSTATE CANCER: CAPSULAR, SEMINAL VESICLE AND LYMPH NODE INVOLVEMENT Knowledge of the spread of cancer beyond the prostate capsule is critical for choosing appropriate therapy. TRUS is a more commonly available imaging method than MRI/MRSI but it is considered by most urologists to be an insensitive method for detecting local extension and predicting clinical stage. MRI has a reported accuracy of 75–90% for staging prostate cancer [32]. Conventional contrast-enhanced MRI has provided no significant advantage in locating cancer within the prostate, or in assessing extraprostatic spread of cancer, with a reported NPV of 67–90% and specificity of 47–100%. Previous histopathological studies have shown that prostate cancer volume is a significant predictor of extracapsular spread. Therefore, tumour volume estimates made on MRSI findings have been used in conjunction with high-specificity MRI criteria to diagnose extracapsular spread, thereby improving the accuracy of MRI in the diagnosis of extracapsular spread. Yu et al. [33] showed that, considering a threshold of 1 mL of tumour volume per lobe as predictive of extracapsular spread, adding MRSI increased the accuracy of MRI from 0.77 to 0.83 in predicting early spread outside the prostate. Hricak et al. [34] reported that the surgical plan should be altered for 39% of the neurovascular bundles at risk on MRI/MRSI examination. In cases with known high-risk disease MRI/MRSI had an even greater effect where it could help to avoid a wide excision of the neurovascular bundle in most cases. STATUS IN DIRECTING TREATMENT BASED ON THE LOCATION OF PROSTATE CANCER: EFFECT ON SURGICAL TECHNIQUE, DIRECTING IMPLANTS FOR BRACHYTHERAPY/CRYOTHERAPY The location of tumour was recently related to the risk of tumour recurrence after prostatectomy, with a higher risk when the surgical margins are positive at the base than at the apex. This could affect the refinements made in surgical technique to reduce positive margins and improve overall oncological outcomes. Preoperative knowledge of tumour location with MRSI could help the surgeon in this regard. In addition, intraglandular localization of prostate cancer has attained importance with the emergence of various disease-targeted therapies, e.g. interstitial brachytherapy, intensity-modulated radiotherapy and cryosurgery. Despite various advances in external beam radiotherapy and brachytherapy, true optimization of dose distributions is still not possible because of uncertainties in tumour position within the prostate. This uncertainty forces the radiation oncologist to deliver the maximum dose to the entire gland, which often results in a higher than optimum dose to the urethra. Although urinary side-effects might be inevitable for patients treated with prostatic implantation, it is hypothesized that with improved optimization techniques and intraoperative correction protocols to further enhance needle distribution and seed placement, these side-effects can be reduced without compromising local control. The MRS-guided plan has been shown to successfully allow increased tumour doses without increasing the maximum urethral dose [35]. STATUS FOR THE FOLLOW-UP OF PROSTATE CANCER FOR DETECTING RECURRENCE Presently PSA is used to follow patients with prostate cancer after any type of therapy (surgery, radiation, hormonal, cryotherapy, etc.). However, PSA is not specific and levels might be increased due to residual BPH tissue. Conventional radiological techniques like TRUS, CT and MRI have very poor accuracy for diagnosing and localizing tumour in this setting, because most therapies cause changes in the tissue that resemble cancer tissue on these imaging studies. Biopsy remains the only definitive means to diagnose residual disease or recurrence, and it is also subject to sampling errors. In this regard, MRSI has been shown to be effective in differentiating between benign, malignant and necrotic tissue after surgical, hormonal, radiation and cryotherapy [9,36–39]. Kurhanewicz et al. [40] used 3D MRSI to investigate the clinical potential for follow-up of the response to cryosurgery and showed its reliability in assessing the presence and the spatial extent of recurrent local disease after therapy. Parivar et al. [39] reported that 3D MRSI was better than TRUS and MRI in differentiating among prostate cancer, BPH © JOURNAL COMPILATION © 2009 THE AUTHORS 2009 BJU INTERNATIONAL MRSI IN THE MANAGEMENT OF PROSTATE CANCER and necrosis when local recurrence after cryosurgery is suspected. Pickett et al. [41] studied MRI/MRSI before and at varying times after external beam radiotherapy, and showed a strong correlation between MRI/MRSI and biopsy findings, whereas there was a very weak correlation with PSA levels. This implies that MRI/MRSI might be useful for detecting residual/recurrent tumour after radiotherapy. A complete metabolic atrophy has shown a NPV of 100% for the presence of local recurrence. FUTURE ADVANCES Clinical MR systems with field strengths ≥3 T can increase the spatial resolution of the data acquired, as well as improve chemical-shift dispersion, thereby reducing the overlap of metabolites in the proton spectrum. Newer metabolic markers might be identified which could provide increased specificity to this technique. Other MR-based imaging techniques, like diffusion-weighted imaging, magnetization transfer imaging, etc., are being developed and could be combined with MRI/MRSI to further improve the accuracy in diagnosis of cancer prostate [42,43]. SUMMARY Currently, various studies on MRSI provide compelling evidence for differentiating malignant from benign tissue. It can be used in combination with other studies to improve various aspects in the management of prostate cancer. 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Eur Biophys J 2005; 32: 761 Correspondence: Rajeev Kumar, Urology, All India Institute of Medical Sciences, New Delhi, India. e-mail: [email protected] Abbreviations: MRSI, MR spectroscopic imaging; NMR, nuclear magnetic resonance; PZ, peripheral zone; TZ, transition zone; PPV/NPV, positive/negative predictive value; RF, radiofrequency; 3D, three-dimensional; TR, repetition time; TE, echo time; SNR, signal-to-noise ratio. © JOURNAL COMPILATION © 2009 THE AUTHORS 2009 BJU INTERNATIONAL