Optimization of the flip angles of narrow-band editing pulses in J-difference edited MRS of lactate at 3T.

PURPOSE: Application of highly selective editing RF pulses provides a means of minimizing co-editing of contaminants in J-difference MRS (MEGA), but it causes reduction in editing yield. We examined the flip angles (FAs) of narrow-band editing pulses to maximize the lactate edited signal with minimal co-editing of threonine. METHODS: The effect of editing-pulse FA on the editing performance was examined, with numerical and phantom analyses, for bandwidths of 17.6-300 Hz in MEGA-PRESS editing of lactate at 3T. The FA and envelope of 46 ms Gaussian editing pulses were tailored to maximize the lactate edited signal at 1.3 ppm and minimize co-editing of threonine. The optimized editing-pulse FA MEGA scheme was tested in brain tumor patients. RESULTS: Simulation and phantom data indicated that the optimum FA of MEGA editing pulses is progressively larger than 180° as the editing-pulse bandwidth decreases. For 46 ms long 17.6 Hz bandwidth Gaussian pulses and other given sequence parameters, the lactate edited signal was maximum at the first and second editing-pulse FAs of 241° and 249°, respectively. The edit-on and difference-edited lactate peak areas of the optimized FA MEGA were greater by 43% and 25% compared to the 180°-FA MEGA, respectively. In-vivo data confirmed the simulation and phantom results. The lesions of the brain tumor patients showed elevated lactate and physiological levels of threonine. CONCLUSION: The lactate MEGA editing yield is significantly increased with editing-pulse FA much larger than 180° when the editing-pulse bandwidth is comparable to the lactate quartet frequency width.

J-Difference editing (MEGA) of lactate in the human brain at 3T.

PURPOSE: The need to detect and quantify brain lactate accurately by MRS has stimulated the development of editing sequences based on J coupling effects. In J-difference editing of lactate, threonine can be co-edited and it contaminates lactate estimates due to the spectral proximity of the coupling partners of their methyl protons. We therefore implemented narrow-band editing 180° pulses (E180) in MEGA-PRESS acquisitions to resolve separately the 1.3-ppm resonances of lactate and threonine. METHODS: Two 45.3-ms rectangular E180 pulses, which had negligible effects 0.15-ppm away from the carrier frequency, were implemented in a MEGA-PRESS sequence with TE 139 ms. Three acquisitions were designed to selectively edit lactate and threonine, in which the E180 pulses were tuned to 4.1 ppm, 4.25 ppm, and a frequency far off resonance. Editing performance was validated with numerical analyses and acquisitions from phantoms. The narrow-band E180 MEGA and another MEGA-PRESS sequence with broad-band E180 pulses were evaluated in six healthy subjects. RESULTS: The 45.3-ms E180 MEGA offered a difference-edited lactate signal with lower intensity and reduced contamination from threonine compared to the broad-band E180 MEGA. The 45.3 ms E180 pulse had MEGA editing effects over a frequency range larger than seen in the singlet-resonance inversion profile. Lactate and threonine in healthy brain were both estimated to be 0.4 ± 0.1 mM, with reference to N-acetylaspartate at 12 mM. CONCLUSION: Narrow-band E180 MEGA editing minimizes threonine contamination of lactate spectra and may improve the ability to detect modest changes in lactate levels.

Optimization of spectrally selective 180° radiofrequency pulse timings in J-difference editing (MEGA) of lactate.

PURPOSE: J-Difference editing (MEGA) provides an effective spectroscopic means of selectively measuring low-concentration metabolites having weakly coupled spins. The fractional inphase and antiphase coherences are determined by the radiofrequency (RF) pulses and inter-RF pulse intervals of the sequence. We examined the timings of the spectrally selective editing 180° pulses (E180) in MEGA-PRESS to maximize the edited signal amplitude in lactate at 3T. METHODS: The time evolution of the lactate spin coherences was analytically and numerically calculated for non-volume localized and single-voxel localized MEGA sequences. Single-voxel localized MEGA-PRESS simulations and phantom experiments were conducted for echo time (TE) 60-160 ms and for all possible integer-millisecond timings of the E180 pulses. Optimized E180 timings of 144, 103, and 109 ms TEs, tailored with simulation and phantom data, were tested in brain tumor patients in vivo. Lactate signals, broadened to singlet linewidths (~6 Hz), were compared between simulation, phantom, and in vivo data. RESULTS: Theoretical and experimental data indicated consistently that the MEGA-edited signal amplitude and width are sensitive to the E180 timings. In volume-localized MEGA, the lactate peak amplitudes in E180-on and difference spectra were maximized at specific E180 timings for individual TEs, largely due to the chemical-shift displacement effects. The E180 timings for maximum lactate peak amplitude were different from those of maximum inphase coherence in in vivo linewidth situations. CONCLUSION: In in vivo MEGA editing, the E180 pulse timings can be effectively used for manipulating the inphase and antiphase coherences and increasing the edited signal amplitude, following TE optimization.

An Efficient Compression Method of Underwater Acoustic Sensor Signals for Underwater Surveillance.

In this paper, we propose a new compression method using underwater acoustic sensor signals for underwater surveillance. Generally, sonar applications that are used for surveillance or ocean monitoring are composed of many underwater acoustic sensors to detect significant sources of sound. It is necessary to apply compression methods to the acquired sensor signals due to data processing and storage resource limitations. In addition, depending on the purposes of the operation and the characteristics of the operating environment, it may also be necessary to apply compression methods of low complexity. Accordingly, in this research, a low-complexity and nearly lossless compression method for underwater acoustic sensor signals is proposed. In the design of the proposed method, we adopt the concepts of quadrature mirror filter (QMF)-based sub-band splitting and linear predictive coding, and we attempt to analyze an entropy coding technique suitable for underwater sensor signals. The experiments show that the proposed method achieves better performance in terms of compression ratio and processing time than popular or standardized lossless compression techniques. It is also shown that the compression ratio of the proposed method is almost the same as that of SHORTEN with a 10-bit maximum mode, and both methods achieve a similar peak signal-to-noise ratio (PSNR) and structural similarity (SSIM) index on average.

Spectral fitting strategy to overcome the overlap between 2-hydroxyglutarate and lipid resonances at 2.25 ppm.

PURPOSE: 1 H MRS provides a noninvasive tool for identifying mutations in isocitrate dehydrogenase (IDH). Quantification of the prominent 2-hydroxyglutarate (2HG) resonance at 2.25 ppm is often confounded by the lipid resonance at the same frequency in tumors with elevated lipids. We propose a new spectral fitting approach to separate these overlapped signals, therefore, improving 2HG evaluation. METHODS: TE 97 ms PRESS was acquired at 3T from 42 glioma patients. New lipid basis sets were created, in which the small lipid 2.25-ppm signal strength was preset with reference to the lipid signal at 0.9 ppm, incorporating published fat relaxation data. LCModel fitting using the new lipid bases (Fitting method 2) was conducted along with fitting using the LCModel built-in lipid basis set (Fitting method 1), in which the lipid 2.25-ppm signal is assessed with reference to the lipid 1.3-ppm signal. In-house basis spectra of low-molecular-weight metabolites were used in both fitting methods. RESULTS: Fitting method 2 showed marked improvement in identifying IDH mutational status compared with Fitting method 1. 2HG estimates from Fitting method 2 were overall smaller than those from Fitting method 1, which was because of differential assignment of the signal at 2.25 ppm to lipids. In receiver operating characteristic analysis, Fitting method 2 provided a complete distinction between IDH mutation and wild-type whereas Fitting method 1 did not. CONCLUSION: The data suggest that 1 H MR spectral fitting using the new lipid basis set provides a robust fitting strategy that improves 2HG evaluation in brain tumors with elevated lipids.

In vivo MRS measurement of 2-hydroxyglutarate in patient-derived IDH-mutant xenograft mouse models versus glioma patients.

PURPOSE: To generate a preclinical model of isocitrate dehydrogenase (IDH) mutant gliomas from glioma patients and design a MRS method to test the compatibility of 2-hydroxyglutarate (2HG) production between the preclinical model and patients. METHODS: Five patient-derived xenograft (PDX) mice were generated from two glioma patients with IDH1 R132H mutation. A PRESS sequence was tailored at 9.4 T, with computer simulation and phantom analyses, for improving 2HG detection in mice. 2HG and other metabolites in the PDX mice were measured using the optimized MRS at 9.4 T and compared with 3 T MRS measurements of the metabolites in the parental-tumor patients. Spectral fitting was performed with LCModel using in-house basis spectra. Metabolite levels were quantified with reference to water. RESULTS: The PRESS TE was optimized to be 96 ms, at which the 2HG 2.25 ppm signal was narrow and inverted, thereby leading to unequivocal separation of the 2HG resonance from adjacent signals from other metabolites. The optimized MRS provided precise detection of 2HG in mice compared to short-TE MRS at 9.4 T. The 2HG estimates in PDX mice were in excellent agreement with the 2HG measurements in the patients. CONCLUSION: The similarity of 2HG production between PDX models and parental-tumor patients indicates that PDX tumors retain the parental IDH metabolic fingerprint and can serve as a preclinical model for improving our understanding of the IDH-mutation associated metabolic reprogramming.

Cumulative burden of inflammation predicts colorectal neoplasia risk in ulcerative colitis: a large single-centre study.

OBJECTIVE: Ulcerative colitis (UC) is a dynamic disease with its severity continuously changing over time. We hypothesised that the risk of colorectal neoplasia (CRN) in UC closely follows an actuarial accumulative inflammatory burden, which is inadequately represented by current risk stratification strategies. DESIGN: This was a retrospective single-centre study. Patients with extensive UC who were under colonoscopic surveillance between 2003 and 2012 were studied. Each surveillance episode was scored for a severity of microscopic inflammation (0=no activity; 1=mild; 2=moderate; 3=severe activity). The cumulative inflammatory burden (CIB) was defined as sum of: average score between each pair of surveillance episodes multiplied by the surveillance interval in years. Potential predictors were correlated with CRN outcome using time-dependent Cox regression. RESULTS: A total of 987 patients were followed for a median of 13 years (IQR, 9-18), 97 (9.8%) of whom developed CRN. Multivariate analysis showed that the CIB was significantly associated with CRN development (HR, 2.1 per 10-unit increase in CIB (equivalent of 10, 5 or 3.3 years of continuous mild, moderate or severe active microscopic inflammation); 95% CI 1.4 to 3.0; P<0.001). Reflecting this, while inflammation severity based on the most recent colonoscopy alone was not significant (HR, 0.9 per-1-unit increase in severity; 95% CI 0.7 to 1.2; P=0.5), a mean severity score calculated from all colonoscopies performed in preceding 5 years was significantly associated with CRN risk (HR, 2.2 per-1-unit increase; 95% CI 1.6 to 3.1; P<0.001). CONCLUSION: The risk of CRN in UC is significantly associated with accumulative inflammatory burden. An accurate CRN risk stratification should involve assessment of multiple surveillance episodes to take this into account.

Evolutionary history of human colitis-associated colorectal cancer.

OBJECTIVE: IBD confers an increased lifetime risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) is molecularly distinct from sporadic CRC (S-CRC). Here we have dissected the evolutionary history of CA-CRC using multiregion sequencing. DESIGN: Exome sequencing was performed on fresh-frozen multiple regions of carcinoma, adjacent non-cancerous mucosa and blood from 12 patients with CA-CRC (n=55 exomes), and key variants were validated with orthogonal methods. Genome-wide copy number profiling was performed using single nucleotide polymorphism arrays and low-pass whole genome sequencing on archival non-dysplastic mucosa (n=9), low-grade dysplasia (LGD; n=30), high-grade dysplasia (HGD; n=13), mixed LGD/HGD (n=7) and CA-CRC (n=19). Phylogenetic trees were reconstructed, and evolutionary analysis used to reveal the temporal sequence of events leading to CA-CRC. RESULTS: 10/12 tumours were microsatellite stable with a median mutation burden of 3.0 single nucleotide alterations (SNA) per Mb, ~20% higher than S-CRC (2.5 SNAs/Mb), and consistent with elevated ageing-associated mutational processes. Non-dysplastic mucosa had considerable mutation burden (median 47 SNAs), including mutations shared with the neighbouring CA-CRC, indicating a precancer mutational field. CA-CRCs were often near triploid (40%) or near tetraploid (20%) and phylogenetic analysis revealed that copy number alterations (CNAs) began to accrue in non-dysplastic bowel, but the LGD/HGD transition often involved a punctuated 'catastrophic' CNA increase. CONCLUSIONS: Evolutionary genomic analysis revealed precancer clones bearing extensive SNAs and CNAs, with progression to cancer involving a dramatic accrual of CNAs at HGD. Detection of the cancerised field is an encouraging prospect for surveillance, but punctuated evolution may limit the window for early detection.

High-Definition Chromoendoscopy Versus High-Definition White Light Colonoscopy for Neoplasia Surveillance in Ulcerative Colitis: A Randomized Controlled Trial.

OBJECTIVES: Although chromoendoscopy is currently the recommended mode of surveillance in patients with long-standing ulcerative colitis, it is technically challenging and requires a long procedure time. The aim of this study was to compare the dysplasia detection rate of high-definition white light endoscopy with random biopsy (HDWL-R) vs high-definition chromoendoscopy with targeted biopsy (HDCE-T). METHODS: This was a multicenter, prospective randomized controlled trial involving 9 tertiary teaching hospitals in South Korea. A total of 210 patients with long-standing ulcerative colitis were randomized to undergo either the HDWL-R group (n = 102) or HDCE-T group (n = 108). The detection rates of colitis-associated dysplasia (CAD) or all colorectal neoplasia from each trial arm were compared. RESULTS: There was no significant difference in the CAD detection rate between HDCE-T and HDWL-R groups (4/102, 3.9% vs 6/108, 5.6%, P = 0.749). However, HDCE-T showed a trend toward improved colorectal neoplasia detection compared with HDWL-R (21/102, 20.6% vs 13/108, 12.0%, P = 0.093). The median (range) time for colonoscopy withdrawal between the 2 groups was similar (17.6 [7.0-43.3] minutes vs 16.5 [6.3-38.1] minutes; P=0.212; for HDWL-R and HDCE-T, respectively). The total number of biopsies was significantly larger in the HDWL-R group (34 [12-72]) compared with the HDCE-T group (9 [1-20]; P < 0.001). DISCUSSION: On the basis of our prospective randomized controlled trial, HDCE-T was not superior to HDWL-R for detecting CADs.

False-Positive Measurement at 2-Hydroxyglutarate MR Spectroscopy in Isocitrate Dehydrogenase Wild-Type Glioblastoma: A Multifactorial Analysis.

Background Isocitrate dehydrogenase (IDH) mutation has become one of the most important prognostic biomarkers in glioma management. Measurement of 2-hydroxyglutarate (2HG) with MR spectroscopy has shown high pooled sensitivity, although false-positive results with MR spectroscopy have been reported. Purpose To investigate factors associated with false-positive 2HG measurements at MR spectroscopy in patients with IDH wild-type glioblastoma. Materials and Methods This retrospective study was approved by the institutional review board, and informed consent was waived. Consecutive patients with histopathologically confirmed pre- and posttreatment glioblastoma were evaluated between December 2017 and August 2018. Spectroscopy parameters, including 2HG measurements, were obtained with single-voxel point-resolved spectroscopy, and apparent diffusion coefficient (ADC) values were calculated. Necrosis was graded according to the proportion of necrosis within a volume of interest. Poisson regression analyses were performed to determine factors related to false-positive 2HG measurements. Results A total of 82 patients were included (mean age, 55 years ± 12 [standard deviation]; 40 men). The 2HG measurement showed a false-positive rate of 21% (17 of 82; 95% CI: 13%, 31%) in patients with IDH wild-type glioblastoma. Multivariable analysis revealed that necrosis (prevalence ratio [PR], 3.9; 95% CI: 1.6, 9.4; P = .01) and ADC value (PR, 0.1 × 10-3 mm2/sec; 95% CI: [0.0, 0.7] × 10-3 mm2/sec; P = .02) were associated with a greater false-positive rate for the 2HG measurement. Necrosis of more than 20% was associated with a higher rate of false-positive 2HG measurements (50%) than was necrosis of 20% or less (15%, P = .01). The 2HG false-positive rate was higher in patients with pretreatment glioblastoma (46%) than in those with posttreatment glioblastoma (14%, P < .01). Among 17 patients with false-positive findings, 15 (88%; 95% CI: 64%, 99%) had a lactate concentration of 2.0 mmol/L or higher, and 14 (82%, 95% CI: 57%, 96%) had a lactate concentration of 3.0 mmol/L or higher. Conclusion Necrosis and apparent diffusion coefficient were associated with false-positive measurements of 2-hydroxyglutarate at MR spectroscopy in patients with isocitrate dehydrogenase wild-type glioblastoma. © RSNA, 2019 Online supplemental material is available for this article.

3D high-resolution imaging of 2-hydroxyglutarate in glioma patients using DRAG-EPSI at 3T in vivo.

PURPOSE: To develop 3D high-resolution imaging of 2-hydroxyglutarate (2HG) at 3T in vivo. METHODS: Echo-planar spectroscopic imaging with dual-readout alternated-gradients (DRAG-EPSI), which was recently reported for 2D imaging of 2HG at 7T, was tested for 3D imaging of 2HG at 3T. The frequency drifts and acoustic noise induced by DRAG-EPSI were investigated in comparison with conventional EPSI. Four patients with IDH-mutant gliomas were enrolled for 3D imaging of 2HG and other metabolites. A previously reported 2HG-tailored TE 97-ms PRESS sequence preceded the DRAG-EPSI readout gradients. Unsuppressed water, acquired with EPSI, was used as reference for multi-channel combination, eddy-current compensation, and metabolite quantification. Spectral fitting was conducted with the LCModel using in-house basis sets. RESULTS: With gradient strength of 4 mT/m and slew rate of 20 mT/m/ms, DRAG-EPSI produced frequency drifts smaller by 5.5-fold and acoustic noise lower by 25 dB compared to conventional EPSI. In a 19-min scan, 3D DRAG-EPSI provided images of 2HG with precision (CRLB <10%) at a resolution of 10 × 10 × 10 mm3 for a field of view of 240 × 180 × 80 mm3 . 2HG was estimated to be 5 mM in a pre-treatment patient. In 3 post-surgery patients, 2HG estimates were 3-6 mM, and the 2HG distribution was different from the water-T2 image pattern or highly concentrated in the post-contrast enhancing region. CONCLUSION: Together with 2HG-optimized PRESS, DRAG-EPSI provides an effective tool for reliable 3D high-resolution imaging of 2HG at 3T in vivo.

Distinction of the GABA 2.29 ppm resonance using triple refocusing at 3 T in vivo.

PURPOSE: To develop 1 H MR spectroscopy that provides distinction of γ-aminobutyric acid (GABA) signal at 3 T in vivo. METHODS: Triple-refocusing was tailored at 3 T, with numerical simulations and phantom validation, for distinction of the GABA 2.29-ppm resonance from the neighboring glutamate resonance. The optimization was performed on the inter-RF pulse time delays and the duration and carrier frequency of a non-slice-selective RF pulse. The optimized triple refocusing was tested in multiple regions in 6 healthy subjects, including hippocampus. The in vivo spectra were analyzed with the LCModel using in-house basis spectra. After normalization of the metabolite signal estimates to water, the metabolite concentrations were quantified with reference to medial-occipital creatine at 8 mM. RESULTS: A triple-refocusing scheme with optimized inter-RF pulse time delays (TE = 74 ms) was obtained for GABA detection. With optimized duration (14 ms) and carrier frequency (4.5 ppm) of the non-slice-selective RF pulse, the triple refocusing gave rise to distinction between the GABA 2.29-ppm and glutamate 2.35-ppm signals. The GABA 2.29-ppm signal was clearly discernible in spectra in vivo (voxel size 4 to 12 mL; scan times 4.3 to 17 minutes). With a total of 24 spectra from 6 gray or white matter-dominant regions, the GABA concentration was measured to be 0.62 to 1.15 mM (Cramer-Rao lower bound of 8 to 14%), and the glutamate level 5.8 to 11.2 mM (Cramer-Rao lower bound of 3 to 6%). CONCLUSION: The optimized triple refocusing provided distinction between GABA and glutamate signals and permitted direct codetection of these metabolites in the human brain at 3 T in vivo.

Echo-planar spectroscopic imaging with dual-readout alternated gradients (DRAG-EPSI) at 7 T: Application for 2-hydroxyglutarate imaging in glioma patients.

PURPOSE: To develop echo-planar spectroscopic imaging (EPSI) with large spectral width and accomplish high-resolution imaging of 2-hydroxyglutarate (2HG) at 7 T. METHODS: We designed a new EPSI readout scheme at 7 T. Data were recorded with dual-readout alternated gradients and combined according to the gradient polarity. Following validation of its performance in phantoms, the new readout scheme, together with previously reported 2HG-optimized magnetic resonance spectroscopy (point-resolved spectroscopy echo time of 78 ms), was used for time-efficient and high-resolution imaging of 2HG and other metabolites in five glioma patients before treatment. Unsuppressed water, acquired with EPSI, was used as reference for multichannel combination, eddy-current compensation, and metabolite quantification. Spectral fitting was conducted with the LCModel using in-house calculated basis sets. RESULTS: Using a readout gradient strength of 9.5 mT/m and slew rate of 90 mT/m/ms, dual-readout alternated gradients EPSI permitted 1638-Hz spectral width with 6 × 6 mm2 in-plane resolution at 7 T. Phantom data indicated that dual-readout alternated gradients EPSI provides proper metabolite signals and induces much less frequency drifts than conventional EPSI. For a spatial resolution of 0.5 mL, 2HG was detected in tumors with precision (Cramer-Rao lower bound < 10%). The 2HG was estimated to be 2.3 to 3.3 mM in tumors of three patients with biopsy-proven isocitrate dehydrogenase (IDH) mutant gliomas. The 2HG was undetectable in an IDH wild-type glioblastoma. For a radiographically suggested glioma, the estimated 2HG of 2.3 ± 0.2 mM (Cramer-Rao lower bound < 10%) indicated that the lesion may be an IDH mutant glioma. CONCLUSIONS: The data indicated that the dual-readout alternated gradients EPSI can provide reliable high-resolution imaging of 2HG in glioma patients at 7 T in vivo. Magn Reson Med 79:1851-1861, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

In vivo detection of 2-hydroxyglutarate in brain tumors by optimized point-resolved spectroscopy (PRESS) at 7T.

PURPOSE: To test the efficacy of 7T MRS for in vivo detection of 2-hydroxyglutarate (2HG) in brain tumors. METHODS: The subecho times of point-resolved spectroscopy (PRESS) were optimized at 7T with density-matrix simulations and phantom validation to improve the 2HG signal selectivity with respect to the neighboring resonances of γ-aminobutyric acid (GABA), glutamate (Glu), and glutamine (Gln). MRS data were acquired from 12 subjects with gliomas in vivo and analyzed with LCModel using calculated basis spectra. Metabolite levels were quantified using unsuppressed short echo time (TE) water as a reference. RESULTS: The PRESS TE was optimized as TE = 78 ms (TE1 = 58 ms and TE2 = 20 ms), at which the 2HG 2.25 ppm resonance appeared as a temporally maximum inverted narrow peak and the GABA, Glu, and Gln resonances between 2.2 and 2.5 ppm were all positive peaks. The PRESS TE = 78 ms method offered improved discrimination of 2HG from Glu, Gln, and GABA when compared with short-TE MRS. 2HG was detected in all patients enrolled in the study, the estimated 2HG concentrations ranging from 1.0 to 6.2 mM, with percentage standard deviation of 2%-7%. CONCLUSION: Data indicate that the optimized MRS provides good selectivity of 2HG from other metabolite signals and may confer reliable in vivo detection of 2HG at relatively low concentrations. Magn Reson Med 77:936-944, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Detection of 2-hydroxyglutarate in brain tumors by triple-refocusing MR spectroscopy at 3T in vivo.

PURPOSE: To test the efficacy of triple-refocusing MR spectroscopy (MRS) for improved detection of 2-hydroxyglutarate (2HG) in brain tumors at 3T in vivo. METHODS: The triple-refocusing sequence parameters were tailored at 3T, with density-matrix simulations and phantom validation, for enhancing the 2HG 2.25-ppm signal selectivity with respect to the adjacent resonances of glutamate (Glu), glutamine (Gln), and gamma-aminobutyric acid (GABA). In vivo MRS data were acquired from 15 glioma patients and analyzed with LCModel using calculated basis spectra. Metabolites were quantified with reference to water. RESULTS: A triple-refocusing sequence (echo time = 137 ms) was obtained for 2HG detection. The 2HG 2.25-ppm signal was large and narrow while the Glu and Gln signals between 2.2 and 2.3 ppm were minimal. The optimized triple refocusing offered improved separation of 2HG from Glu, Gln and GABA when compared with published MRS methods. 2HG was detected in all 15 patients, the estimated 2HG concentrations ranging from 2.4 to 15.0 mM, with Cramer-Rao lower bounds of 2%-11%. The 2HG estimates did not show significant correlation with total choline. CONCLUSION: The optimized triple refocusing provides excellent 2HG signal discrimination from adjacent resonances and may confer reliable in vivo measurement of 2HG at relatively low concentrations. Magn Reson Med 78:40-48, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Measurement of glycine in healthy and tumorous brain by triple-refocusing MRS at 3 T in vivo.

Glycine (Gly) has been implicated in several neurological disorders, including malignant brain tumors. The precise measurement of Gly is challenging largely as a result of the spectral overlap with myo-inositol (mI). We report a new triple-refocusing sequence for the reliable co-detection of Gly and mI at 3 T and for the evaluation of Gly in healthy and tumorous brain. The sequence parameters were optimized with density-matrix simulations and phantom validation. With a total TE of 134 ms, the sequence gave complete suppression of the mI signal between 3.5 and 3.6 ppm and, consequently, well-defined Gly (3.55 ppm) and mI (3.64 ppm) peaks. In vivo 1 H magnetic resonance spectroscopy (MRS) data were acquired from the gray matter (GM)-dominant medial occipital and white matter (WM)-dominant left parietal regions in six healthy subjects, and analyzed with LCModel using in-house-calculated basis spectra. Tissue segmentation was performed to obtain the GM and WM contents within the MRS voxels. Metabolites were quantified with reference to GM-rich medial occipital total creatine at 8 mM. The Gly and mI concentrations were estimated to be 0.63 ± 0.05 and 8.6 ± 0.6 mM for the medial occipital and 0.34 ± 0.05 and 5.3 ± 0.8 mM for the left parietal regions, respectively. From linear regression of the metabolite estimates versus fractional GM content, the concentration ratios between pure GM and pure WM were estimated to be 2.6 and 2.1 for Gly and mI, respectively. Clinical application of the optimized sequence was performed in four subjects with brain tumor. The Gly levels in tumors were higher than those of healthy brain. Gly elevation was more extensive in a post-contrast enhancing region than in a non-enhancing region. The data indicate that the optimized triple-refocusing sequence may provide reliable co-detection of Gly and mI, and alterations of Gly in brain tumors can be precisely evaluated.

In vivo (1)H MRSI of glycine in brain tumors at 3T.

PURPOSE: MR spectroscopic imaging (SI) of glycine (Gly) in the human brain is challenging due to the interference of the abundant neighboring J-coupled resonances. Our aim is to accomplish reliable imaging of Gly in healthy brain and brain tumors using an optimized MR sequence scheme at 3 tesla. METHODS: Two-dimensional (1)H SI was performed with a point-resolved spectroscopy scheme. An echo time of 160 ms was used for separation between Gly and myo-inositol signals. Data were collected from eight healthy volunteers and 14 subjects with gliomas. Spectra were analyzed with the linear combination model using numerically calculated basis spectra. Metabolite concentrations were estimated with reference to creatine in white matter (WM) regions at 6.4 molar concentrations (mM). RESULTS: From a linear regression analysis with respect to the fractional gray matter (GM) content, the Gly concentrations in pure GM and WM in healthy brains were estimated to be 1.1 and 0.3 mM, respectively. Gly was significantly elevated in tumors. The tumor-to-contralateral Gly concentration ratio was more extensive with higher grades, showing ∼ 10-fold elevation of Gly in glioblastomas. CONCLUSION: The Gly level is significantly different between GM and WM in healthy brains. Our data indicate that SI of Gly may provide a biomarker of brain tumor malignancy.

Forty-Year Analysis of Colonoscopic Surveillance Program for Neoplasia in Ulcerative Colitis: An Updated Overview.

OBJECTIVES: This study provides an overview of the largest and longest-running colonoscopic surveillance program for colorectal cancer (CRC) in patients with long-standing ulcerative colitis (UC). METHODS: Data were obtained from medical records, endoscopy, and histology reports. Primary end points were defined as death, colectomy, withdrawal from surveillance, or censor date (1 January 2013). RESULTS: A total of 1,375 UC patients were followed up for 15,234 patient-years (median, 11 years per patient). CRC was detected in 72 patients (incidence rate (IR), 4.7 per 1,000 patient-years). Time-trend analysis revealed that although there was significant decrease in incidence of colectomy performed for dysplasia (linear regression, R=-0.43; P=0.007), IR of advanced CRC and interval CRC have steadily decreased over past four decades (Pearson's correlation, -0.99; P=0.01 for both trends). The IR of early CRC has increased 2.5-fold in the current decade compared with past decade (χ(2), P=0.045); however, its 10-year survival rate was high (79.6%). The IR of dysplasia has similarly increased (χ(2), P=0.01), potentially attributable to the recent use of chromoendoscopy that was twice more effective at detecting dysplasia compared with white-light endoscopy (χ(2), P<0.001). CRCs were frequently accompanied by synchronous CRC or spatially distinct dysplasia (37.5%). Finally, the risk of CRC was not significantly different between "indefinite" or low-grade dysplasia (log-rank, P=0.78). CONCLUSIONS: Colonoscopic surveillance may have a significant role in reducing the risk of advanced and interval CRC while allowing more patients to retain their colon for longer. Given the ongoing risk of early CRC, patients with any grade of dysplasia who are managed endoscopically should be monitored closely with advanced techniques.

Low-grade dysplasia in ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer.

OBJECTIVES: The aim of this study was to identify risk factors associated with development of high-grade dysplasia (HGD) or colorectal cancer (CRC) in ulcerative colitis (UC) patients diagnosed with low-grade dysplasia (LGD). METHODS: Patients with histologically confirmed extensive UC, who were diagnosed with LGD between 1993 and 2012 at St Mark's Hospital, were identified and followed up to 1 July 2013. Demographic, endoscopic, and histological data were collected and correlated with the development of HGD or CRC. RESULTS: A total of 172 patients were followed for a median of 48 months from the date of initial LGD diagnosis (interquartile range (IQR), 15-87 months). Overall, 33 patients developed HGD or CRC (19.1% of study population; 20 CRCs) during study period. Multivariate Cox proportional hazard analysis revealed that macroscopically non-polypoid (hazard ratio (HR), 8.6; 95% confidence interval (CI), 3.0-24.8; P<0.001) or invisible (HR, 4.1; 95% CI, 1.3-13.4; P=0.02) dysplasia, dysplastic lesions ≥1 cm in size (HR, 3.8; 95% CI, 1.5-13.4; P=0.01), and a previous history of "indefinite for dysplasia" (HR, 2.8; 95% CI, 1.2-6.5; P=0.01) were significant contributory factors for HGD or CRC development. Multifocal dysplasia (HR, 3.9; 95% CI, 1.9-7.8; P<0.001), metachronous dysplasia (HR, 3.5; 95% CI, 1.6-7.5; P=0.001), or a colonic stricture (HR, 7.4; 95% CI, 2.5-22.1; P<0.001) showed only univariate correlation to development of HGD or CRC. CONCLUSIONS: Lesions that are non-polypoid or endoscopically invisible, large (≥1 cm), or preceded by indefinite dysplasia are independent risk factors for developing HGD or CRC in UC patients diagnosed with LGD.