Determinación espacial del estado de los conocimientos El criterio de la accesibilidad

Thirteen patients with a suspicion of PCa and one patient known to have prostate cancer participated in this study (mean age: 59 years; range, 47-74 years; mean weight: 82 kg; range 70-100 kg; and median prostate specific antigen (PSA) level 11 ng/mL; range 4.1-28 ng/mL. The institutional ethics review board waived the need for informed consent for this study.

All patients underwent 3D-1_{H-MRSI as an addition to a clinical mpMRI exam,}

consisting of high resolution T2-weighted imaging (T2W) in three orthogonal directions, diffusion weighted imaging (DWI) and dynamic contrast enhanced imaging (DCE). MRSI measurements were performed prior to contrast agent administration. All exams were performed on 3T MR systems (Magnetom Skyra, Siemens Healthcare, Erlangen, Germany) using an 18-channel body phased array coil and a 32-channel spine phased array coil for signal reception, and no ERC. Peristaltic motion was reduced by intramuscular injections of 20 mg butylscopalmine bromide (Buscopan, Boehringer Ingelheim, Ingelheim, Germany) and 1 mg glucagon (GlucaGen, Novo Nordisk, Gentofte, Denmark)

127

prior to the exam. One of the patients did not receive glucagon because of allergy.

1_{H 3D-MR spectroscopic imaging}

For MR spectroscopy measurements a non-product 3D-MRSI sequence with sLASER volume selection using GOIA-Wurst(16,4) refocusing pulses and a TE of 88 ms was used [18]. To suppress peri-prostatic lipid signals, 5 outer volume saturation (OVS) bands were placed over the corners of the selection box. All measurements were performed with weighted elliptical k-space sampling with 3 averages and a 100% Hamming filter. A pre-scan normalize filter was used to optimize the combination of signals from the individual coil elements. Measurements were performed at various TRs (from 630 to 1000 ms) and at two spatial resolutions to verify the effects of these parameters on the spectral quality and the percentage of reliably fitted metabolite signals (see table 1). Measurements at a nominal spatial resolution of 7×7×7 mm3 _{(n=11) were}

performed using a field of view (FOV) of 84×70×70 mm3 _{and a matrix of}

12×10×10. The effective spherical voxel volume at 64% of the point spread function maximum with a 100% Hanning k-space filter is about 0.9 cc[19, 22]. Measurements at a nominal spatial resolution of 6×6×6 mm3 _{(n=3) were}

performed using an FOV of 84×60×72 mm3 _{and a matrix of 14×10×12,}

resulting in an effective spherical voxel volume of about 0.6 cc.

No pre-processing of the spectral data was applied and after interpolation to a matrix size of 16x16x16 and fourier transform all spectra were fitted employing LCModel [23] using a sequence-specific basis set containing model signals of Cit, Cr, Spm and Cho, simulated with NMR Sim (Bruker Corporation, Billerica, MA, USA). In each voxel, the relative tissue concentration of each metabolite was estimated, as well as the Cramér Rao Lower Bound (CRLB) on these estimates.

Chapter 7

128

Matrix Size Nominal voxel size (mm3₎ TR (ms) TA (min:sec) Group 1 1,2 84×70×70 12×10×10 7×7×7 630 4:50 3,4,5 84×70×70 12×10×10 7×7×7 800 6:09 6 84×70×70 12×10×10 7×7×7 820 6:45 7,8 84×70×70 12×10×10 7×7×7 900 6:55 9,10 84×70×70 12×10×10 7×7×7 1000 7:43 Group 2 11 84×60×72 14×10×12 6×6×6 740 8:11 12,13 84×60×72 14×10×12 6×6×6 900 9:57

Table 1 3D 1_{H MRSI measurement parameters for 13 subjects with suspected prostate cancer.}

All measurements were performed with TE = 88 ms and 3 averages. Variable TRs and voxel sizes resulted in different acquisition times TA.

Spectral quality assessment

To assess spectral quality, the central 6×6 voxels in 3 adjacent transversal slices (i.e. 108 voxels) at the level of the prostate mid-gland were selected in each patient. The percentage of selected voxels in which the metabolite was fitted with a CRLB <30% was recorded for each patient and each metabolite. To facilitate a comparison we followed the voxel selection and quality assessment of a previous study, in which an ERC was used [18].

Metabolite maps

The MR images, spectra and LCModel quantification outputs were transferred to a workstation with home-built processing and display software implemented in MeVisLab (Version 2.5a, MeVis Medical Solutions AG, Bremen, Germany). Metabolite maps of Cho and Cit were generated using the tissue levels estimated in each interpolated voxel by LCModel.

Statistical analysis

Statistical analyses were performed in Graphpad Prism version 5.03 for Windows (GraphPad Software, San Diego, CA, USA). In each patient and for each metabolite, the percentage of selected voxels in which the metabolite

129

was fitted with a CRLB <30% was recorded. The average and standard deviation (SD) of these percentages were calculated separately for each nominal voxel size.

Results

The patients suspected to have PCa received PIRADS scores of 2 (n=8), 3 (n=4) and 4 (n=1), based on their mpMRI examination. Only the patient scored as PIRADS 4 underwent an MR-guided biopsy, in which no malignant tissue was detected by standard histopathology. All 3D-1_{H-MRSI measurements were}

completed in less than 10 minutes. The acquisition times (TA), ranging from 4:50 min to 9:57 min, were not SAR limited in any of the patients. The performance of the GOIA-sLASER MRSI without an ERC is demonstrated by typical MR spectra, spectral maps and Cit metabolite maps of two patients with suspected PCa in Fig. 1. These two patients were measured with different TRs, but equal matrix size, FOV and number of averages. Good quality spectra with reliably fitted citrate peaks (CLRB <15%) were achieved in the peripheral zone (PZ) and transition zone (TZ), at a TR of 1000 ms with a TA of 7:43 min (Fig. 1 a- d) and at a TR of 630 ms with a TA of 4:50 min (Fig. 1 e-h). Except for some signal intensity at about 2.4 ppm, obvious lipid signal contamination in the spectral region of interest (2.4 - 3.4ppm) was not observed (Fig. 1b, c, f, g). In accordance with the clinical assessment of these patients, including mpMRI, which revealed no malignancies, the MRSI data did not show clearly increased Cho and decreased Cit signals, as biomarkers for the presence of cancer foci. As the Cho signal, of which an increase is a hallmark for tumor presence, becomes saturated by 40 to 60% at the TRs employed in the current study, it may not always be clearly visible (SNR ˃2) in apparently normal prostate tissue (see Fig. 1g). Therefore, it is relevant to demonstrate that an increased Cho in PCa tissue can be detected without use of an ERC. This is demonstrated for a patient with biopsy proven PCa (Fig. 2). Cit was not detected in any of the 3D MRSI voxels, which may be due to the hormone therapy this patient was receiving, or to the presence of tumor, or both. However, a clear signal

Chapter 7

130

assigned to Cho is detected in voxels throughout the prostate (Fig. 2c), in particular in areas with low ADC values (see Fig. 2b and d).

Spectral quality

For a quantitative evaluation of the performance of GOIA-sLASER 3D MRSI exams without ERC we assessed the CRLB of the main prostate metabolite resonances in spectra of 13 patients that were suspected to have PCa, but with negative biopsies (Fig. 3). The Cit signal was reliably detected in almost all spectra, with CRLBs<30% in 100% of 7×7×7 mm3 _{voxels and 96 ± 7% in}

6×6×6 mm3 _{voxels. In spite of its relative low concentration in this patient}

population, Cho was detected with a CRLB<30% in 76 ± 23 % and 46 ± 38% in voxels with nominal resolutions of 7×7×7mm3 _{and 6×6×6mm}3_{, respectively. Cr}

and Spm also showed a higher fitting reliability at the larger voxel size (Fig. 3).