Quality control of prostate 1 H MRSI data

MRSI of prostate cancer provides a potential clinical tool to aid in the detection and characterisation of this disease, but its clinical use is limited by the need for the specialist training of radiologists to read these datasets. An essential part of this reading is the assessment of the usability and reliability of MRSI spectra because they can be affected by artefacts such as poor signal to noise, lipid signal contamination and broad resonances that could cause errors of interpretation. We have developed an automated quality control algorithm that classifies every voxel of an MRSI dataset as either acceptable or unacceptable for further analysis, based on the spectral profile alone. The method was trained and tested based on a gold standard of agreement of four experts. It was highly accurate: testing with a novel set of data from MRSI patients produced agreement with the experts' consensus decisions with a specificity of 0.95 and sensitivity of 0.95. This method provides fast quality control of three‐dimensional MRSI datasets of the prostate, removing the need for radiologists to perform this time consuming, but necessary, task prior to further analysis. Copyright © 2012 John Wiley & Sons, Ltd.     

Quantification of prostate MRSI data by model-based time domain fitting and frequency domain analysis

This paper compares two spectral processing methods for obtaining quantitative measures from in vivo prostate spectra, evaluates their effectiveness, and discusses the necessary modifications for accurate results. A frequency domain analysis (FDA) method based on peak integration was compared with a time domain fitting (TDF) method, a model-based nonlinear least squares fitting algorithm. The accuracy of both methods at estimating the choline + creatine + polyamines to citrate ratio (CCP:C) was tested using Monte Carlo simulations, empirical phantom MRSI data and in vivo MRSI data. The paper discusses the different approaches employed to achieve the quantification of the overlapping choline, creatine and polyamine resonances. Monte Carlo simulations showed induced biases on the estimated CCP:C ratios. Both methods were successful in identifying tumor tissue, provided that the CCP:C ratio was greater than a given (normal) threshold. Both methods predicted the same voxel condition in 94% of the in vivo voxels (68 out of 72). Both TDF and FDA methods had the ability to identify malignant voxels in an artifact-free case study using the estimated CCP:C ratio. Comparing the ratios estimated by the TDF and the FDA, the methods predicted the same spectrum type in 17 out of 18 voxels of the in vivo case study (94.4%).     

Composite slice‐selective adiabatic excitation for prostate MRSI

Higher magnetic field strengths, such as 7 T, offer increased spectral resolution and higher signal‐to‐noise ratio. These properties can be very advantageous for MRSI. In particular, signals that generally overlap at lower fields, such as choline, polyamines and creatine, can be resolved at 7 T. However, higher magnetic field strengths suffer from strong radiofrequency (RF) field nonuniformities. These nonuniformities become even stronger when using surface transceivers, such as an endorectal coil for prostate imaging. In order to obtain uniform excitations for accurate MRSI measurements, adiabatic sequences are therefore recommended. Conventional adiabatic MRS sequences (i.e. localization by adiabatic selective refocusing, LASER) have relatively long TEs, especially when optimized to measure the strongly coupled spins of citrate in the prostate. The semi‐LASER (sLASER) sequence has a significantly shorter TE, although it does not provide adiabatic excitation. Therefore, we propose an adiabatic sLASER sequence that either has a composite adiabatic slice‐selective excitation (cLASER) or a non‐slice‐selective adiabatic excitation (nsLASER), allowing for shorter TEs, whilst maintaining the adiabatic spin excitation. Furthermore, the spatial properties of the composite adiabatic excitation allow for a high slice excitation bandwidth, resulting in negligible chemical shift displacement artifacts. Exclusion of the slice selection can be considered once the field of view extends beyond the transmit field of the RF coil. The use of a transceiver at high magnetic field strengths has shown that the cLASER and nsLASER sequences are suitable for MRSI of the prostate in both phantom and in vivo validations. Copyright © 2012 John Wiley & Sons, Ltd.     

Hierarchical non‐negative matrix factorization applied to three‐dimensional 3 T MRSI data for automatic tissue characterization of the prostate

In this study non‐negative matrix factorization (NMF) was hierarchically applied to simulated and in vivo three‐dimensional 3 T MRSI data of the prostate to extract patterns for tumour and benign tissue and to visualize their spatial distribution. Our studies show that the hierarchical scheme provides more reliable tissue patterns than those obtained by performing only one NMF level. We compared the performance of three different NMF implementations in terms of pattern detection accuracy and efficiency when embedded into the same kind of hierarchical scheme. The simulation and in vivo results show that the three implementations perform similarly, although one of them is more robust and better pinpoints the most aggressive tumour voxel(s) in the dataset. Furthermore, they are able to detect tumour and benign tissue patterns even in spectra with lipid artefacts. Copyright © 2016 John Wiley & Sons, Ltd.     

Automatic quality control in clinical 1H MRSI of brain cancer

MRSI grids frequently show spectra with poor quality, mainly because of the high sensitivity of MRS to field inhomogeneities. These poor quality spectra are prone to quantification and/or interpretation errors that can have a significant impact on the clinical use of spectroscopic data. Therefore, quality control of the spectra should always precede their clinical use. When performed manually, quality assessment of MRSI spectra is not only a tedious and time‐consuming task, but is also affected by human subjectivity. Consequently, automatic, fast and reliable methods for spectral quality assessment are of utmost interest. In this article, we present a new random forest‐based method for automatic quality assessment of ¹H MRSI brain spectra, which uses a new set of MRS signal features. The random forest classifier was trained on spectra from 40 MRSI grids that were classified as acceptable or non‐acceptable by two expert spectroscopists. To account for the effects of intra‐rater reliability, each spectrum was rated for quality three times by each rater. The automatic method classified these spectra with an area under the curve (AUC) of 0.976. Furthermore, in the subset of spectra containing only the cases that were classified every time in the same way by the spectroscopists, an AUC of 0.998 was obtained. Feature importance for the classification was also evaluated. Frequency domain skewness and kurtosis, as well as time domain signal‐to‐noise ratios (SNRs) in the ranges 50–75 ms and 75–100 ms, were the most important features. Given that the method is able to assess a whole MRSI grid faster than a spectroscopist (approximately 3 s versus approximately 3 min), and without loss of accuracy (agreement between classifier trained with just one session and any of the other labelling sessions, 89.88%; agreement between any two labelling sessions, 89.03%), the authors suggest its implementation in the clinical routine. The method presented in this article was implemented in jMRUI's SpectrIm plugin. Copyright © 2016 John Wiley & Sons, Ltd.     

Evaluation of short‐TE 1H MRSI for quantification of metabolites in the prostate

Back‐to‐back ¹H MRSI scans, using an endorectal and phased‐array coil combination, were performed on 18 low‐risk patients with prostate cancer at 3 T, employing TEs of 32 and 100 ms in order to compare metabolite visualization at each TE. Outer‐volume suppression of lipid signals was performed using regional saturation (REST) slabs and the quantification of spectra at both TEs was achieved with the quantitation using quantum estimation (QUEST) routine. Metabolite nulling experiments in an additional five patients found that there were negligible macromolecule background signals in prostate spectra at TE = 32 ms. Metabolite visibility was judged using the criterion Cramér–Rao lower bound (CRLB)/amplitude < 20%, and metabolite concentrations were corrected for relaxation effects and referenced to the data acquired in corresponding water‐unsuppressed MRSI scans. For the first time, the prostate metabolites spermine and myo‐inositol were quantified individually in vivo, together with citrate, choline and creatine. All five metabolite visibilities were higher in TE = 32 ms MRSI than in TE = 100 ms MRSI. At TE = 32 ms, citrate was visible in 99.0% of lipid‐free spectra, whereas, at TE = 100 ms, no metabolite simulation of citrate matched the in vivo peaks. Spermine, choline and creatine were visualised separately in 30.4% more spectra at TE = 32 ms than at TE = 100 ms, and myo‐inositol in 72.5% more spectra. T₂ values were calculated for spermine (53 ± 16 ms), choline (62 ± 17 ms) and myo‐inositol (90 ± 48 ms). Data from the TE = 32 ms spectra showed that the concentrations of citrate and spermine secretions were positively correlated in both the peripheral zone and central gland (R² = 0.73 and R² = 0.43, respectively), and that the citrate content was significantly higher in the former at 64 ± 22 mm than in the latter at 32 ± 16 mm (p = 0.01). However, lipid contamination at TE = 32 ms was substantial; therefore, to make clinical use of the greater visualisation of prostate metabolites at TE = 32 ms rather than at TE = 100 ms, three‐dimensional MRSI at TE = 32 ms with effective lipid suppression must be implemented. ©2014 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd.     

Lactate MRSI and DCE MRI as surrogate markers of prostate tumor aggressiveness

Longitudinal studies of lactate MRSI and dynamic contrast-enhanced MRI were performed at 4.7 T in two prostate tumor models grown in rats, Dunning R3327-AT (AT) and Dunning R3327-H (H), to determine the potential of lactate and the perfusion/permeability parameter Ak(ep) as markers of tumor aggressiveness. Subcutaneous AT (n = 12) and H (n = 6) tumors were studied at different volumes between 100 and 2900 mm(3) (Groups 1-5). Lactate concentration was determined using selective multiple quantum coherence MRSI with the phantom substitution method. Tumor enhancement after the administration of gadolinium diethylenetriaminepenta-acetic acid was analyzed using the Brix-Hoffmann model and the Ak(ep) parameter was used as a measure of tumor perfusion/permeability. Lactate was not detected in the smallest AT tumors (Group 1; 100-270 mm(3) ). In larger AT tumors, the lactate concentration increased from 2.8 ± 1.0 mm (Group 2; 290-700 mm(3)) to 8.4 ± 2.9 mm (Group 3; 1000-1340 mm(3)) and 8.2 ± 2.2 mm (Group 4; 1380-1750 mm(3) ), and then decreased to 5.0 ± 1.7 mm (Group 5; 1900-2500 mm(3)), and was consistently higher in the tumor core than in the rim. Lactate was not detected in any of the H tumors. The mean tumor Ak(ep) values decreased with increasing volume in both tumor types, but were significantly higher in H tumors. In AT tumors, the Ak(ep) values were significantly higher in the rim than in the core. Histological hypoxic and necrotic fractions in AT tumors increased with volume from 0% in Group 1 to about 20% and 30%, respectively, in Group 5. Minimal amounts of hypoxia and necrosis were found in H tumors of all sizes. Thus, the presence of lactate and heterogeneous perfusion/permeability are signatures of aggressive, metabolically deprived tumors.     

Temporal B0 field variation effects on MRSI of the human prostate at 7 T and feasibility of correction using an internal field probe

Spectral degradations as a result of temporal field variations are observed in MRSI of the human prostate. Moving organs generate substantial temporal and spatial field fluctuations as a result of susceptibility mismatch with the surrounding tissue (i.e. periodic breathing, cardiac motion or random bowel motion). Nine patients with prostate cancer were scanned with an endorectal coil (ERC) on a 7‐T MR scanner. Temporal B₀ field variations were observed with fast dynamic B₀ mapping in these patients. Simulations of dynamic B₀ corrections were performed using zero‐ to second‐order shim terms. In addition, the temporal B₀ variations were applied to simulated MR spectra causing, on average, 15% underestimation of the choline/citrate ratio. Linewidth distortions and frequency shifts (up to 30 and 8 Hz, respectively) were observed. To demonstrate the concept of observing local field fluctuations in real time during MRSI data acquisition, a field probe (FP) tuned and matched for the ¹⁹ F frequency was incorporated into the housing of the ERC. The data acquired with the FP were compared with the B₀ field map data and used to correct the MRSI datasets retrospectively. The dynamic B₀ mapping data showed variations of up to 30 Hz (0.1 ppm) over 72 s at 7 T. The simulated zero‐order corrections, calculated as the root mean square, reduced the standard deviation (SD) of the dynamic variations by an average of 41%. When using second‐order corrections, the reduction in the SD was, on average, 56%. The FP data showed the same variation range as the dynamic B₀ data and the variation patterns corresponded. After retrospective correction, the MRSI data showed artifact reduction and improved spectral resolution. B₀ variations can degrade the MRSI substantially. The simple incorporation of an FP into an ERC can improve prostate cancer MRSI without prior knowledge of the origin of the dynamic field distortions. Copyright © 2014 John Wiley & Sons, Ltd.     

Analysis of metabolic abnormalities in high‐grade glioma using MRSI and convex NMF

Clinical use of MRSI is limited by the level of experience required to properly translate MRSI examinations into relevant clinical information. To solve this, several methods have been proposed to automatically recognize a predefined set of reference metabolic patterns. Given the variety of metabolic patterns seen in glioma patients, the decision on the optimal number of patterns that need to be used to describe the data is not trivial. In this paper, we propose a novel framework to (1) separate healthy from abnormal metabolic patterns and (2) retrieve an optimal number of reference patterns describing the most important types of abnormality. Using 41 MRSI examinations (1.5 T, PRESS, T_E 135 ms) from 22 glioma patients, four different patterns describing different types of abnormality were detected: edema, healthy without Glx, active tumor and necrosis. The identified patterns were then evaluated on 17 MRSI examinations from nine different glioma patients. The results were compared against BraTumIA, an automatic segmentation method trained to identify different tumor compartments on structural MRI data. Finally, the ability to predict future contrast enhancement using the proposed approach was also evaluated.     

Distribution and secretory pathways of prostate specific antigen,alpha1-antichymotrypsin and prostate secretory granules in prostate cancers

Using 19 radical prostatectomy specimens, we studied the histological distribution of free prostate specific antigen (PSA), total PSA, alpha1-antichymotrypsin (ACT) and prostate secretory granules (PSG) in both normal and cancerous cells of the prostate. After glutaraldehyde fixation, numerous fine eosinophilic droplets of PSG could be found mainly in the apical portions of normal acinous epithelial cells, but was markedly decreased in cancer cells. With antibodies against free PSA, normal acinous cells were granularly positive in the apical portion of the epithelium, which corresponded to the PSG, whereas cancer cells were diffusely positive. With antibodies against ACT, normal duct cells and cancer cells were often positive, but few normal acinous cells were positive. Presumably, these findings indicate that free PSA is secreted into the lumen as PSG in normal glands, but not by the same pathway in cancers where free PSA appears to accumulate due to a decrease of PSG, then leak into the blood producing complexed PSA to some extent in the cytoplasm. One factor analysis of variance (ANOVA) on the correlation of tumor differentiation or Gleason score with serum values of total PSA, free PSA and a free/total PSA ratio demonstrated no significant links. Elucidation of secretory mechanisms should provide better comprehension of various PSA indices for prostate cancer screening.     

Clinical utility of pathology data: prostate and kidney cancer

Cancer pathology reports can be complex due to multiple data elements, variability in terminology, and increasing recognition of emerging diagnostic entities. However, treatment may be significantly influenced by histologic subtype, histologic grade, and pathologic tumor stage. We review the clinical utility of pathology data for prostate and kidney cancers, with emphasis on main decision-making points. Key parameters that affect management of prostate cancer in the biopsy setting include Grade Group, percentage of pattern 4, and sometimes extent of involvement. Histologic subtypes mostly do not affect management, with exceptions of small cell carcinoma and sometimes cribriform/intraductal carcinoma. For renal cancer, histologic subtype, tumor grade, and tumor stage are important for prognostication. Confirming a diagnosis of renal cell carcinoma and recognition of clear cell, non-clear cell, and select other histologies are important in the metastatic setting for treatment selection.     

Histone H1 expression in human prostate cancer tissues and cell lines

Histone H1, one of the histone superfamilies, is known to determine chromatin structure and alter gene expression. It also contributes to regulation of cell proliferation in breast cancer. We hypothesized a similar association in prostate cancer, and therefore examined relationships between histone H1 expression and Gleason pattern, Ki-67 and androgen receptor levels in a series of prostate cancer tissues and cell lines. Histone H1 positive cancer cells increased with the Gleason pattern. Gleason pattern 3 tumors were divided into two groups, one with high histone H1 positivity (H1-high cases, 60-100% positivity) and the other with low histone H1 positivity (H1-low cases, 0-20% positivity). Ki-67 or androgen receptor positivity in H1-high cases was significantly higher than in H1-low cases. PC3 cells demonstrated more frequent histone H1 and Ki-67 positivity as compared to LNCaP cells. Silencing of histone H1 by siRNA transfection significantly reduced cell proliferation in LNCaP and PC3. These findings suggest that histone H1 expression is associated with the Gleason pattern, cell proliferation and androgen receptor expression in prostate cancers.     

Relevance of cohort design for studying the frequency of the ERG rearrangement in prostate cancer

Braun M, Scheble V J, Menon R, Scharf G, Wilbertz T, Petersen K, Beschorner C, Reischl M, Kuefer R, Schilling D, Stenzl A, Kristiansen G, Rubin M A, Fend F & Perner S
(2011) Histopathology 58 , 1028–1036
Relevance of cohort design for studying the frequency of the ERG rearrangement in prostate cancer Aims: ERG rearrangements, mostly resulting in TMPRSS2–ERG fusions, are frequentalterations in prostate cancer (PCa), with a frequency ranging from 15% to 78%. As the reason for this variability is unknown, our aim was to investigate the ERG rearrangement frequency with a cohort design. Methods and results: We assessed three well‐defined cohorts for ERG rearrangements, using fluorescence in situ hybridization (FISH). The first cohort comprised 119 prostatectomy specimens. The second and third cohorts included incidentally diagnosed PCa [71 cystoprostatectomy specimens, and 105 transurethral resection of the prostate (TURP) specimens]. Seventy of 119 (59%) cases of the prostatectomy cohort harboured ERG rearrangements. Regarding zonal origin, 2/11 (18%) transition zone (TZ) foci and 75/145 (52%) peripheral zone (PZ) foci harboured ERG rearrangements. Within the cystoprostatectomies, 24/71 (34%) cases harboured ERG rearrangements. Regarding zonal origin, 2/9 (22%) TZ foci and 26/86 (30%) PZ foci harboured ERG rearrangements. PCa incidentally identified by TURP harboured ERG rearrangements in 31/105 (29%) cases. Conclusions: ERG rearrangements occur in TZ PCa, although at a lower frequency than in PZ PCa. We confirmed that approximately half of all prostatectomies harbour ERG rearrangements. However, the frequency in incidentally diagnosed PCa cohorts was significantly lower, even if multifocality was considered. Consequently, zonal origin and cohort design are key for studying the clinical implications of ERG rearrangements.     

前列腺癌非编码RNA1在雄激素非依赖去势抵抗型前列腺癌细胞中的作用

目的 探讨长链非编码RNA前列腺癌非编码RNA1(PRNCR1)在雄激素非依赖的前列腺癌细胞中的作用.方法 应用实时定量PCR(qRT-PCR)检测雄激素依赖的前列腺癌细胞LNCaP及雄激素非依赖的前列腺癌细胞C4-2中PRNCR1的表达情况,通过RNA干扰技术沉默C4-2细胞中的PRNCR1,Western blot技术检测C4-2细胞中雄激素受体(AR)的表达变化,流式细胞术检测细胞凋亡的变化,MTT实验检测沉默PRNCR1表达对细胞增殖的影响,Transwell侵袭实验检测细胞侵袭能力的变化.结果 PRNCR1在雄激素非依赖的细胞系C4-2中高表达,干扰其表达可以明显降低前列腺癌细胞中AR的表达,抑制前列腺癌细胞的细胞增殖及细胞的侵袭能力,并促进细胞的凋亡.结论 PRNCR1介导AR在前列腺癌去势抵抗中发挥着重要作用.     

PIM-1蛋白激酶在前列腺癌组织中的表达

目的观察原癌基因PIM1表达产物PIM1蛋白激酶在前列腺癌组织、良性前列腺增生组织及正常前列腺组织中的表达。方法应用免疫组织化学方法测定37例前列腺癌组织、26例良性前列腺增生组织及12例正常前列腺组织中PIM1蛋白激酶的表达。结果PIM1蛋白激酶在前列腺癌组织、良性前列腺增生组织及正常前列腺组织中的阳性表达例数分别是29例(78.38%),11例(42.31%)和3例(25.00%)。前列腺癌组PIM1的表达显著高于良性前列腺增生组及正常前列腺组(P<0.001)。结论原癌基因PIM1及其产物PIM1蛋白激酶有可能在前列腺癌的发生发展中发挥重要作用。     

VERDICT MRI validation in fresh and fixed prostate specimens using patient‐specific moulds for histological and MR alignment

The VERDICT framework for modelling diffusion MRI data aims to relate parameters from a biophysical model to histological features used for tumour grading in prostate cancer. Validation of the VERDICT model is necessary for clinical use. This study compared VERDICT parameters obtained ex vivo with histology in five specimens from radical prostatectomy. A patient‐specific 3D‐printed mould was used to investigate the effects of fixation on VERDICT parameters and to aid registration to histology. A rich diffusion data set was acquired in each ex vivo prostate before and after fixation. At both time points, data were best described by a two‐compartment model: the model assumes that an anisotropic tensor compartment represents the extracellular space and a restricted sphere compartment models the intracellular space. The effect of fixation on model parameters associated with tissue microstructure was small. The patient‐specific mould minimized tissue deformations and co‐localized slices, so that rigid registration of MRI to histology images allowed region‐based comparison with histology. The VERDICT estimate of the intracellular volume fraction corresponded to histological indicators of cellular fraction, including high values in tumour regions. The average sphere radius from VERDICT, representing the average cell size, was relatively uniform across samples. The primary diffusion direction from the extracellular compartment of the VERDICT model aligned with collagen fibre patterns in the stroma obtained by structure tensor analysis. This confirmed the biophysical relationship between ex vivo VERDICT parameters and tissue microstructure from histology.     

前列腺特异性抗原EIA试剂盒的研制及应用

目的 建立可定量测定人血清中前列腺特异性抗原（ＰＳＡ）含量的夹心ＥＬＩＳＡ法,研制ＰＳＡ－ＥＩＡ检测试剂盒。方法 从健康男性精液中提取并纯化ＰＳＡ,分别免疫Ｂａｌｂ／ｃ小鼠和山羊制备特异性单克隆抗体和多克隆抗体,并以纯化的ＰＳＡ为标准品,建立可定量测定血清中ＰＳＡ含量的夹心ＥＬＩＳＡ法。在此基础上组装ＰＳＡ－ＥＩＡ试剂盒,对该试剂盒的特异性、灵敏度、精密度、正确性和稳定性等多项指标进行评价。应用该     

IL-6/JAK/STAT3信号通路在前列腺癌发展和治疗中的研究进展

IL-6/JAK/STAT3是IL-6激活的显著的信号通路之一。IL-6、p-STAT3在前列腺癌(PCa)组织和转移瘤中高表达,在诱导PCa发生、促进肿瘤细胞增殖、侵袭和转移中起着关键作用,并且通过激活雄激素受体(AR)参与PCa去势抵抗和肿瘤耐药。IL-6/JAK/STAT3及其激活的下游因子在肿瘤进展中的多种角色为化疗药物开发提供了良好的基础,目前,许多靶向抑制剂已被证明可有效抑制肿瘤进展,有望研发出更多有效药物。     

Proton spectroscopic imaging of the human prostate at 7 T

The sensitivity of proton MR Spectroscopic Imaging (¹H‐MRSI) of the prostate can be optimized by using the high magnetic field strength of 7 T in combination with an endorectal coil. In the work described in this paper we introduce an endorectal transceiver at 7 T, validate its safety for in vivo use and apply a pulse sequence, optimized for three‐dimensional (3D) ¹H‐MRSI of the human prostate at 7 T. A transmit/receive endorectal RF coil was adapted from a commercially available 3 T endorectal receive‐only coil and validated to remain within safety guidelines for radiofrequency (RF) power deposition using numerical models, MR thermometry of phantoms, and in vivo temperature measurements. The ¹H‐MRSI pulse sequence used adiabatic slice selective refocusing pulses and frequency‐selective water and lipid suppression to selectively obtain the relevant metabolite signals from the prostate. Quantum mechanical simulations were used to adjust the inter‐pulse timing for optimal detection of the strongly coupled spin system of citrate resulting in an echo time of 56 ms. Using this endorectal transceiver and pulse sequence with slice selective adiabatic refocusing pulses, 3D ¹H‐MRSI of the human prostate is feasible at 7 T with a repetition time of 2 s. The optimized inter‐pulse timing enables the absorptive detection of resonances of spins from spermine and citrate in phase with creatine and choline. These potential tumor markers may improve the in vivo detection, localization, and assessment of prostate cancer. Copyright © 2009 John Wiley & Sons, Ltd.