Four-quadrant vector mapping of hybrid multidimensional MRI data for the diagnosis of prostate cancer.

PURPOSE: The interpretation of prostate multiparametric magnetic resonance imaging (MRI) is subjective in nature, and there is large inter-observer variability among radiologists and up to 30% of clinically significant cancers are missed. This has motivated the development of new MRI techniques and sequences, especially quantitative approaches to improve prostate cancer diagnosis. Using hybrid multidimensional MRI, apparent diffusion coefficient (ADC) and T2 have been shown to change as a function of echo time (TE) and b-values, and that this dependence is different for cancer and benign tissue, which can be exploited for prostate cancer diagnosis. The purpose of this study is to investigate whether four-quadrant vector mapping of hybrid multidimensional MRI (HM-MRI) data can be used to diagnose prostate cancer (PCa) and determine cancer aggressiveness. METHODS: Twenty-one patients with confirmed PCa underwent preoperative MRI prior to radical prostatectomy. Axial HM-MRI were acquired with all combinations of TE = 47, 75, 100 ms and b-values of 0, 750, 1500 s/mm2 , resulting in a 3 × 3 data matrix associated with each voxel. Prostate Quadrant (PQ) mapping analysis represents HM-MRI data for each voxel as a color-coded vector in the four-quadrant space of HM-MRI parameters (a 2D matrix of signal values for each combination of b-value and TE) with associated amplitude and angle information representing the change in T2 and ADC as a function of b-value and TE, respectively. RESULTS: Cancers have a higher PQ4 (22.50% ± 21.27%) and lower PQ2 (69.86% ± 28.24%) compared to benign tissue: peripheral, transition, and central zone (PQ4 = 0.13% ± 0.56%, 5.73% ± 15.07%, 2.66% ± 4.05%, and PQ2 = 98.51% ± 3.05%, 86.18% ± 21.75%, 93.38% ± 9.88%, respectively). Cancers have a higher vector angle (206.5 ± 41.8°) and amplitude (0.017 ± 0.013) compared to benign tissue. PQ metrics showed moderate correlation with Gleason score (|ρ| = 0.388-0.609), with more aggressive cancers being associated with increased PQ4 and angle and reduced PQ2 and amplitude. A combination of four-quadrant analysis metrics provided an area under the curve of 0.904 (p < 0.001) for the differentiation of prostate cancer from benign prostatic tissue. CONCLUSIONS: Four-quadrant vector mapping of HM-MRI data provides effective cancer markers, with cancers associated with high PQ4 and high vector angle and lower PQ2 and vector amplitude.

A radiomics based method for prediction of prostate cancer Gleason score using enlarged region of interest.

BACKGROUND: Prostate cancer (PCa) is one of the most common cancers in men worldwide, and its timely diagnosis and treatment are becoming increasingly important. MRI is in increasing use to diagnose cancer and to distinguish between non-clinically significant and clinically significant PCa, leading to more precise diagnosis and treatment. The purpose of this study is to present a radiomics-based method for determining the Gleason score (GS) for PCa using tumour heterogeneity on multiparametric MRI (mp-MRI). METHODS: Twenty-six patients with biopsy-proven PCa were included in this study. The quantitative T2 values, apparent diffusion coefficient (ADC) and signal enhancement rates (α) were calculated using multi-echo T2 images, diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE-MRI), for the annotated region of interests (ROI). After texture feature analysis, ROI range expansion and feature filtering was performed. Then obtained data were put into support vector machine (SVM), K-Nearest Neighbor (KNN) and other classifiers for binary classification. RESULTS: The highest classification accuracy was 73.96% for distinguishing between clinically significant (Gleason 3 + 4 and above) and non-significant cancers (Gleason 3 + 3) and 83.72% for distinguishing between Gleason 3 + 4 from Gleason 4 + 3 and above, which was achieved using initial ROIs drawn by the radiologists. The accuracy improved when using expanded ROIs to 80.67% using SVM and 88.42% using Bayesian classification for distinguishing between clinically significant and non-significant cancers and Gleason 3 + 4 from Gleason 4 + 3 and above, respectively. CONCLUSIONS: Our results indicate the research significance and value of this study for determining the GS for prostate cancer using the expansion of the ROI region.

Prostate Cancers Invisible on Multiparametric MRI: Pathologic Features in Correlation with Whole-Mount Prostatectomy.

We investigated why some prostate cancers (PCas) are not identified on multiparametric MRI (mpMRI) by using ground truth reference from whole-mount prostatectomy specimens. A total of 61 patients with biopsy-confirmed PCa underwent 3T mpMRI followed by prostatectomy. Lesions visible on MRI prospectively or retrospectively identified after correlating with histology were considered "identified cancers" (ICs). Lesions that could not be identified on mpMRI were considered "unidentified cancers" (UCs). Pathologists marked the Gleason score, stage, size, and density of the cancer glands and performed quantitative histology to calculate the tissue composition. Out of 115 cancers, 19 were unidentified on MRI. The UCs were significantly smaller and had lower Gleason scores and clinical stage lesions compared with the ICs. The UCs had significantly (p < 0.05) higher ADC (1.34 ± 0.38 vs. 1.02 ± 0.30 µm2/ms) and T2 (117.0 ± 31.1 vs. 97.1 ± 25.1 ms) compared with the ICs. The density of the cancer glands was significantly (p = 0.04) lower in the UCs. The percentage of the Gleason 4 component in Gleason 3 + 4 lesions was nominally (p = 0.15) higher in the ICs (20 ± 12%) compared with the UCs (15 ± 8%). The UCs had a significantly lower epithelium (32.9 ± 21.5 vs. 47.6 ± 13.1%, p = 0.034) and higher lumen volume (20.4 ± 10.0 vs. 13.3 ± 4.1%, p = 0.021) compared with the ICs. Independent from size and Gleason score, the tissue composition differences, specifically, the higher lumen and lower epithelium in UCs, can explain why some of the prostate cancers cannot be identified on mpMRI.

Suppression of Tumor Cell Lactate-generating Signaling Pathways Eradicates Murine PTEN/p53-deficient Aggressive-variant Prostate Cancer via Macrophage Phagocytosis.

PURPOSE: Phosphatase and tensin homolog (PTEN) loss-of-function/PI3K pathway hyperactivation is associated with poor therapeutic outcomes and immune checkpoint inhibitor resistance across multiple malignancies. Our prior studies in Pb-Cre;PTENfl/flTrp53fl/fl genetically engineered mice (GEM) with aggressive-variant prostate cancer (AVPC) demonstrated tumor growth control in 60% mice following androgen deprivation therapy/PI3K inhibitor (PI3Ki)/programmed cell death protein 1 (PD-1) antibody combination, via abrogating lactate cross-talk between cancer cells and tumor-associated macrophages (TAM), and suppression of histone lactylation (H3K18lac)/phagocytic activation within TAM. Here, we targeted immunometabolic mechanism(s) of PI3Ki resistance, with the goal of durable tumor control in AVPC. EXPERIMENTAL DESIGN: Pb-Cre;PTENfl/flTrp53fl/fl GEM were treated with PI3Ki (copanlisib), MEK inhibitor (trametinib) or Porcupine inhibitor (LGK'974) singly or their combinations. MRI was used to monitor tumor kinetics and immune/proteomic profiling/ex vivo coculture mechanistic studies were performed on GEM tumors or corresponding tumor-derived cell lines. RESULTS: Given our proteomic profiling showing persistent MEK signaling within tumors of PI3Ki-resistant GEM, we tested whether addition of trametinib to copanlisib enhances tumor control in GEM, and we observed 80% overall response rate via additive suppression of lactate within TME and H3K18lac within TAM, relative to copanlisib (37.5%) monotherapy. The 20% resistant mice demonstrated feedback Wnt/ß-catenin activation, resulting in restoration of lactate secretion by tumor cells and H3K18lac within TAM. Cotargeting Wnt/ß-catenin signaling with LGK'974 in combination with PI3Ki/MEKi, demonstrated durable tumor control in 100% mice via H3K18lac suppression and complete TAM activation. CONCLUSIONS: Abrogation of lactate-mediated cross-talk between cancer cells and TAM results in durable ADT-independent tumor control in PTEN/p53-deficient AVPC, and warrants further investigation in clinical trials.

Bilateral asymmetry of quantitative parenchymal kinetics at ultrafast DCE-MRI predict response to neoadjuvant chemotherapy in patients with HER2+ breast cancer.

PURPOSE: To assess whether measurement of the bilateral asymmetry of semiquantitative and quantitative perfusion parameters from ultrafast dynamic contrast-enhanced MRI (DCE-MRI), allows early prediction of pathologic response after neoadjuvant chemotherapy (NAC) in patients with HER2+ breast cancer. MATERIALS AND METHODS: Twenty-eight female patients with HER2+ breast cancer treated with NAC who underwent pre-NAC ultrafast DCE-MRI (3-9 s/phase) were enrolled for this study. Four semiquantitative and two quantitative parenchymal parameters were calculated for each patient. Ipsilateral/contralateral (I/C) ratio (for four parameters) and the difference between (for two parameters) ipsi- and contra-lateral parenchymal kinetic parameters (kBPE) were compared for patients with pathologic complete response (pCR) and those having residual disease. Lasso regression with leave-one-out cross validation was used to determine the optimal combination of parameters for a regression model and multivariable logistic regression was used to identify independent predictors for pCR. Chi-squared test, two-sided t-test and Kruskal-Wallis test were used. RESULTS: The Ktrans I/C ratio cutoff value of 1.11 had a sensitivity of 83.3% and specificity of 75% for pCR. The ve I/C ratio cutoff value of 1.1 had a sensitivity of 75% and specificity of 81.3% for pCR. The area under the receiver operating characteristic curve of the three-kBPE parameter model, including initial area under the enhancement curve (AUC30) I/C ratio, KtransI/C ratio and ve I/C ratio, was 0.89 with sensitivity of 91.7% at specificity of 81.3%. CONCLUSION: Quantitative assessment of bilateral asymmetry kBPE from pre-NAC ultrafast DCE-MRI can predict pCR in patients with HER2+ breast cancer.

Parametric maps of spatial two-tissue compartment model for prostate dynamic contrast enhanced MRI - comparison with the standard tofts model in the diagnosis of prostate cancer.

The spatial two-tissue compartment model (2TCM) was used to analyze prostate dynamic contrast enhanced (DCE) MRI data and compared with the standard Tofts model. A total of 29 patients with biopsy-confirmed prostate cancer were included in this IRB-approved study. MRI data were acquired on a Philips Achieva 3T-TX scanner. After T2-weighted and diffusion-weighted imaging, DCE data using 3D T1-FFE mDIXON sequence were acquired pre- and post-contrast media injection (0.1 mmol/kg Multihance) for 60 dynamic scans with temporal resolution of 8.3 s/image. The 2TCM has one fast ([Formula: see text] and [Formula: see text]) and one slow ([Formula: see text] and [Formula: see text]) exchanging compartment, compared with the standard Tofts model parameters (Ktrans and kep). On average, prostate cancer had significantly higher values (p < 0.01) than normal prostate tissue for all calculated parameters. There was a strong correlation (r = 0.94, p < 0.001) between Ktrans and [Formula: see text] for cancer, but weak correlation (r = 0.28, p < 0.05) between kep and [Formula: see text]. Average root-mean-square error (RMSE) in fits from the 2TCM was significantly smaller (p < 0.001) than the RMSE in fits from the Tofts model. Receiver operating characteristic (ROC) analysis showed that fast [Formula: see text] had the highest area under the curve (AUC) than any other individual parameter. The combined four parameters from the 2TCM had a considerably higher AUC value than the combined two parameters from the Tofts model. The 2TCM is useful for quantitative analysis of prostate DCE-MRI data and provides new information in the diagnosis of prostate cancer.

Suppression of tumor cell lactate-generating signaling pathways eradicates murine PTEN/p53-deficient aggressive-variant prostate cancer via macrophage phagocytosis.

Purpose: PTEN loss-of-function/PI3K pathway hyperactivation occurs in ∼50% of metastatic, castrate-resistant prostate cancer patients, resulting in poor therapeutic outcomes and resistance to immune checkpoint inhibitors across multiple malignancies. Our prior studies in prostate-specific PTEN/p53-deleted genetically engineered mice (Pb-Cre;PTEN fl/fl Trp53 fl/fl GEM) with aggressive-variant prostate cancer (AVPC) demonstrated feedback Wnt/ß-catenin signaling activation in 40% mice resistant to androgen deprivation therapy (ADT)/PI3K inhibitor (PI3Ki)/PD-1 antibody (aPD-1) combination, resulting in restoration of lactate cross-talk between tumor-cells and tumor-associated macrophages (TAM), histone lactylation (H3K18lac) and phagocytic suppression within TAM. Here, we targeted immunometabolic mechanism(s) of resistance to ADT/PI3Ki/aPD-1 combination, with the goal of durable tumor control in PTEN/p53-deficient PC. Experimental design: Pb-Cre;PTEN fl/fl Trp53 fl/fl GEM were treated with either ADT (degarelix), PI3Ki (copanlisib), aPD-1, MEK inhibitor (trametinib) or Porcupine inhibitor (LGK 974) as single agents or their combinations. MRI was used to monitor tumor kinetics and immune/proteomic profiling/ ex vivo co-culture mechanistic studies were performed on prostate tumors or established GEM-derived cell lines. Results: We tested whether Wnt/ß-catenin pathway inhibition with LGK 974 addition to degarelix/copanlisib/aPD-1 therapy enhances tumor control in GEM, and observed de novo resistance due to feedback activation of MEK signaling. Based on our observation that degarelix/aPD-1 treatment resulted in partial inhibition of MEK signaling, we substituted trametinib for degarelix/aPD-1 treatment, and observed a durable tumor growth control of PI3Ki/MEKi/PORCNi in 100% mice via H3K18lac suppression and complete TAM activation within TME. Conclusions: Abrogation of lactate-mediated cross-talk between cancer cells and TAM results in durable ADT-independent tumor control in PTEN/p53-deficient AVPC, and warrants further investigation in clinical trials. STATEMENT OF TRANSLATIONAL RELEVANCE: PTEN loss-of-function occurs in ∼50% of mCRPC patients, and associated with poor prognosis, and immune checkpoint inhibitor resistance across multiple malignancies. Our prior studies have demonstrated that ADT/PI3Ki/PD-1 triplet combination therapy controls PTEN/p53-deficient PC in 60% of mice via enhancement of TAM phagocytosis. Here, we discovered that resistance to ADT/PI3K/PD-1 therapy occurred via restoration of lactate production via feedback Wnt/MEK signaling following treatment with PI3Ki, resulting in inhibition of TAM phagocytosis. Critically, co-targeting of PI3K/MEK/Wnt signaling pathways using an intermittent dosing schedule of corresponding targeted agents resulted in complete tumor control and significantly prolonged survival without significant long-term toxicity. Collectively, our findings provide "proof-of-concept" that targeting lactate as a macrophage phagocytic checkpoint controls growth of murine PTEN/p53-deficient PC and warrant further investigation in AVPC clinical trials.

Standardization of Breast Dynamic Contrast-enhanced MRI Signal with Application to the Assessment of Background Parenchymal Enhancement Rate.

BACKGROUND: There is currently no clinically accepted method for quantifying background parenchymal enhancement (BPE), though a sensitive method might allow individualized risk management based on the response to cancer-preventative hormonal therapy. OBJECTIVE: The objective of this pilot study is to demonstrate the utility of linear modeling of standardized dynamic contrast-enhanced MRI (DCEMRI) signal for quantifying changes in BPE rates. METHODS: On a retrospective database search, 14 women with DCEMRI examinations pre- and post- treatment with tamoxifen were identified. DCEMRI signal was averaged over the parenchymal ROIs to obtain time-dependent signal curves S(t). The gradient echo signal equation was used to standardize scale S(t) to values of (FA) ̃ = 10° and (TR) ̃ = 5.5 ms, and obtain the standardized parameters of DCE-MRI signal S ̃_p (t). Relative signal enhancement (〖RSE〗_p ) ̃ was calculated from S ̃_p, and the reference tissue method for T1 calculation was used to standardize (〖RSE〗_p ) ̃ to gadodiamide as the contrast agent, obtaining (RSE) ̃. (RSE) ̃, in the first 6 minutes, post-contrast administration was fit to a linear model with the slope α ̃_RSE denoting the standardized rate relative BPE. RESULTS: Changes in α ̃_RSE were not found to be significantly correlated with the average duration of tamoxifen treatment, age at the initiation of preventative treatment, or pre-treatment BIRADS breast density category. The average change in α ̃_RSE showed a large effect size of -1.12, significantly higher than -0.86 observed without signal standardization (p < 0.01). CONCLUSION: Linear modeling of BPE in standardized DCEMRI can provide quantitative measurements of BPE rates, improving sensitivity to changes due to tamoxifen treatment.

Reversal of Lactate and PD-1-mediated Macrophage Immunosuppression Controls Growth of PTEN/p53-deficient Prostate Cancer.

PURPOSE: Phosphatase and tensin homolog (PTEN) loss of function occurs in approximately 50% of patients with metastatic castrate-resistant prostate cancer (mCRPC), and is associated with poor prognosis and responsiveness to standard-of-care therapies and immune checkpoint inhibitors. While PTEN loss of function hyperactivates PI3K signaling, combinatorial PI3K/AKT pathway and androgen deprivation therapy (ADT) has demonstrated limited anticancer efficacy in clinical trials. Here, we aimed to elucidate mechanism(s) of resistance to ADT/PI3K-AKT axis blockade, and to develop rational combinatorial strategies to effectively treat this molecular subset of mCRPC. EXPERIMENTAL DESIGN: Prostate-specific PTEN/p53-deficient genetically engineered mice (GEM) with established 150-200 mm3 tumors, as assessed by ultrasound, were treated with either ADT (degarelix), PI3K inhibitor (copanlisib), or anti-PD-1 antibody (aPD-1), as single agents or their combinations, and tumors were monitored by MRI and harvested for immune, transcriptomic, and proteomic profiling, or ex vivo co-culture studies. Single-cell RNA sequencing on human mCRPC samples was performed using 10X Genomics platform. RESULTS: Coclinical trials in PTEN/p53-deficient GEM revealed that recruitment of PD-1-expressing tumor-associated macrophages (TAM) thwarts ADT/PI3Ki combination-induced tumor control. The addition of aPD-1 to ADT/PI3Ki combination led to TAM-dependent approximately 3-fold increase in anticancer responses. Mechanistically, decreased lactate production from PI3Ki-treated tumor cells suppressed histone lactylation within TAM, resulting in their anticancer phagocytic activation, which was augmented by ADT/aPD-1 treatment and abrogated by feedback activation of Wnt/ß-catenin pathway. Single-cell RNA-sequencing analysis in mCRPC patient biopsy samples revealed a direct correlation between high glycolytic activity and TAM phagocytosis suppression. CONCLUSIONS: Immunometabolic strategies that reverse lactate and PD-1-mediated TAM immunosuppression, in combination with ADT, warrant further investigation in patients with PTEN-deficient mCRPC.

Parametric maps of spatial two-tissue compartment model for prostate dynamic contrast enhanced MRI - comparison with the standard Tofts model in the diagnosis of prostate cancer.

The spatial two-tissue compartment model (2TCM) was used to analyze prostate dynamic contrast enhanced (DCE) MRI data and compared with the standard Tofts model. A total of 29 patients with biopsy-confirmed prostate cancer were included in this IRB-approved study. MRI data were acquired on a Philips Achieva 3T-TX scanner. After T2-weighted and diffusion-weighted imaging, DCE data using 3D T1-FFE mDIXON sequence were acquired pre- and post-contrast media injection (0.1 mmol/kg Multihance) for 60 dynamic scans with temporal resolution of 8.3 s/image. The 2TCM has one fast (K 1 trans and k 1 ep ) and one slow (K 2 trans and k 2 ep ) exchanging compartment, compared with the standard Tofts model parameters (K trans and k ep ). On average, prostate cancer had significantly higher values (p < 0.007) than normal prostate tissue for all calculated parameters. There was a strong correlation (r = 0.94, p < 0.0001) between K trans and K 1 trans for cancer, but weak correlation (r = 0.28, p < 0.05) between k ep and k 1 ep . Average root-mean-square error (RMSE) in fits from the 2TCM was significantly smaller (p < 0.001) than the RMSE in fits from the Tofts model. Receiver operating characteristic (ROC) analysis showed that fast K 1 trans had the highest area under the curve (AUC) than any other individual parameter. The combined four parameters from the 2TCM had a considerably higher AUC value than the combined two parameters from the Tofts model. The 2TCM may be useful for quantitative analysis of prostate DCE-MRI data and may provide new information in the diagnosis of prostate cancer.

Limosilactobacillus reuteri normalizes blood-brain barrier dysfunction and neurodevelopment deficits associated with prenatal exposure to lipopolysaccharide.

Maternal immune activation (MIA) derived from late gestational infection such as seen in chorioamnionitis poses a significantly increased risk for neurodevelopmental deficits in the offspring. Manipulating early microbiota through maternal probiotic supplementation has been shown to be an effective means to improve outcomes; however, the mechanisms remain unclear. In this study, we demonstrated that MIA modeled by exposing pregnant dams to lipopolysaccharide (LPS) induced an underdevelopment of the blood vessels, an increase in permeability and astrogliosis of the blood-brain barrier (BBB) at prewean age. The BBB developmental and functional deficits early in life impaired spatial learning later in life. Maternal Limosilactobacillus reuteri (L. reuteri) supplementation starting at birth rescued the BBB underdevelopment and dysfunction-associated cognitive function. Maternal L. reuteri-mediated alterations in ß-diversity of the microbial community and metabolic responses in the offspring provide mechanisms and potential targets for promoting BBB integrity and long-term neurodevelopmental outcomes.

The optimal 18F-fluoromisonidazole PET threshold to define tumor hypoxia in preclinical squamous cell carcinomas using pO2 electron paramagnetic resonance imaging as reference truth.

PURPOSE: To identify the optimal threshold in 18F-fluoromisonidazole (FMISO) PET images to accurately locate tumor hypoxia by using electron paramagnetic resonance imaging (pO2 EPRI) as ground truth for hypoxia, defined by pO2 [Formula: see text] 10 mmHg. METHODS: Tumor hypoxia images in mouse models of SCCVII squamous cell carcinoma (n = 16) were acquired in a hybrid PET/EPRI imaging system 2 h post-injection of FMISO. T2-weighted MRI was used to delineate tumor and muscle tissue. Dynamic contrast enhanced (DCE) MRI parametric images of Ktrans and ve were generated to model tumor vascular properties. Images from PET/EPR/MRI were co-registered and resampled to isotropic 0.5 mm voxel resolution for analysis. PET images were converted to standardized uptake value (SUV) and tumor-to-muscle ratio (TMR) units. FMISO uptake thresholds were evaluated using receiver operating characteristic (ROC) curve analysis to find the optimal FMISO threshold and unit with maximum overall hypoxia similarity (OHS) with pO2 EPRI, where OHS = 1 shows perfect overlap and OHS = 0 shows no overlap. The means of dice similarity coefficient, normalized Hausdorff distance, and accuracy were used to define the OHS. Monotonic relationships between EPRI/PET/DCE-MRI were evaluated with the Spearman correlation coefficient ([Formula: see text]) to quantify association of vasculature on hypoxia imaged with both FMISO PET and pO2 EPRI. RESULTS: FMISO PET thresholds to define hypoxia with maximum OHS (both OHS = 0.728 [Formula: see text] 0.2) were SUV [Formula: see text] 1.4 [Formula: see text] SUVmean and SUV [Formula: see text] 0.6 [Formula: see text] SUVmax. Weak-to-moderate correlations (|[Formula: see text]|< 0.70) were observed between PET/EPRI hypoxia images with vascular permeability (Ktrans) or fractional extracellular-extravascular space (ve) from DCE-MRI. CONCLUSION: This is the first in vivo comparison of FMISO uptake with pO2 EPRI to identify the optimal FMISO threshold to define tumor hypoxia, which may successfully direct hypoxic tumor boosts in patients, thereby enhancing tumor control.

Directional and inter-acquisition variability in diffusion-weighted imaging and editing for restricted diffusion.

PURPOSE: To evaluate and quantify inter-directional and inter-acquisition variation in diffusion-weighted imaging (DWI) and emphasize signals that report restricted diffusion to enhance cancer conspicuity, while reducing the effects of local microscopic motion and magnetic field fluctuations. METHODS: Ten patients with biopsy-proven prostate cancer were studied under an Institutional Review Board-approved protocol. Individual acquisitions of DWI signal intensities were reconstructed to calculate inter-acquisition distributions and their statistics, which were compared for healthy versus cancer tissue. A method was proposed to detect and filter the acquisitions affected by motion-induced signal loss. First, signals that reflect restricted diffusion were separated from the acquisitions that suffer from signal loss, likely due to microscopic motion, by imposing a cutoff value. Furthermore, corrected apparent diffusion coefficient maps were calculated by employing a weighted sum of the multiple acquisitions, instead of conventional averaging. These weights were calculated by applying a soft-max function to the set of acquisitions per-voxel, making the analysis immune to acquisitions with significant signal loss, even if the number of such acquisitions is high. RESULTS: Inter-acquisition variation is much larger than the Rician noise variance, local spatial variations, and the estimates of diffusion anisotropy based on the current data, as well as the published values of anisotropy. The proposed method increases the contrast for cancers and yields a sensitivity of 98 . 8 % $$ 98.8\% $$ with a false positive rate of 3 . 9 % $$ 3.9\% $$ . CONCLUSION: Motion-induced signal loss makes conventional signal-averaging suboptimal and can obscure signals from areas with restricted diffusion. Filtering or weighting individual acquisitions prior to image analysis can overcome this problem.

Physically implausible signals as a quantitative quality assessment metric in prostate diffusion-weighted MR imaging.

PURPOSE: To provide a quantitative assessment of diffusion-weighted MR images of the prostate through identification of PIDS which clearly represents artifacts in the data. We calculated the percentage and distribution of PIDS in prostate DWI and compare the amount of PIDS between mpMRI images obtained with and without an endorectal coil. METHODS: This IRB approved retrospective study (from 03/03/2014 to 03/10/2020), included 40 patients scanned with endorectal coil (ERC) and 40 without ER coil (NERC). PIDS contains any voxel where: (1) the diffusion signal increases despite an increase in b-value; and/or (2) apparent diffusion coefficient (ADC) is more than 3.0 µm2/ms (the ADC of pure water at 37 °C and it is physically implausible for any material to have a higher ADC). PIDS for transition zone (TZ) and peripheral zone (PZ) was calculated using an in-house MATLAB program. DWI images were quantitatively inspected for noise, motion, and distortion. T-test was used to compare the difference between PIDS levels in ERC versus NERC and ANOVA to compare the PIDS levels in the anatomic zones. The images were evaluated by a fellowship-trained radiologist in Abdominal Imaging with more than 10 years of experience in reading prostate MRI. This was tested only in prostate in this study. RESULTS: 80 patients (58 ± 8 years old, 80 men) were evaluated. The percentage of voxels exhibiting PIDS was 17.1 ± 8.1% for the ERC cohort and 22.2 ± 15.5% for the NERC cohort. PIDS for NERC versus ERC were not significantly different (p = 0.14). The apex and base showed similar percentages of PIDS in ERC (p = 0.30) and NERC (p = 0.86). The mid (13.8 ± 8.6%) in ERC showed lower values (p = 0.02) of PIDS compared to apex (19.9 ± 11.1%) and base (17.5 ± 8.3%). CONCLUSION: PIDS maps provide a spatially resolved quantitative quality assessment for prostate DWI. Average PIDS over the entire prostate were similar for the ERC and NERC cohorts, and did not differ significantly across prostate zones. However, for many of the patients, PIDS was focally much higher in specific prostate zones. PIDS assessment can guide Radiologist's evaluation of images and the development of improved DWI sequences.

Effectiveness of Dynamic Contrast Enhanced MRI with a Split Dose of Gadoterate Meglumine for Detection of Prostate Cancer.

RATIONALE AND OBJECTIVES: To evaluate whether dynamic contrast enhanced (DCE) MRI with a split injection of 30% followed by 70% of a standard dose (30PSD and 70PSD) of gadoterate meglumine (DOTAREM) can improve diagnosis of prostate cancer (PCa). MATERIALS AND METHODS: MRI for twenty patients was performed on a Philips Ingenia 3T scanner without an endorectal coil followed by subsequent radical prostatectomy. DCE 3D T1-FFE data were acquired with injection of 0.03 mmol/kg followed after 2 minutes by 0.07 mmol/kg of DOTAREM. Regions-of-interest on histologically verified PCa and normal tissue in different prostate zones and the iliac artery were drawn. Average signal intensity as function of time was calculated for each ROI and fitted by using the signal intensity form of the Tofts (SI-Tofts) model to extract physiological parameters (Ktrans and ve). In addition, the scaled arterial input function (AIF) obtained from 30PSD data was used to analyze 70PSD data. RESULTS: The AIF obtained from 30PSD data showed both first and second passes clearly and had much higher peak magnitude than AIFs from 70PSD data. Ktrans was significantly (p < 0.05) larger in PCa than in normal tissue in peripheral zone (PZ) and central zone (CZ) for both 70PSD and 70PSD data analyzed with a scaled AIF. Ktrans in cancer overlapped with that of normal tissue in the transition zone (TZ). There was no statistical difference in ve between cancer and normal tissue. Receiver operating characteristic analysis showed that use of the AIF from 30PSD data to analyze 70PSD data increased the diagnostic efficacy of Ktrans in the PZ and CZ. CONCLUSION: The split dose protocol for injection of Dotarem increased diagnostic accuracy of quantitative analysis with the SI-Tofts model.

Can Pre-treatment Quantitative Multi-parametric MRI Predict the Outcome of Radiotherapy in Patients with Prostate Cancer?

RATIONALE AND OBJECTIVES: To investigate whether pre-treatment quantitative multiparametric MRI can predict biochemical outcome of prostate cancer (PCa) patients treated with primary radiotherapy (RT). MATERIALS AND METHODS: Fifty-one patients with biopsy confirmed PCa underwent prostate multiparametric MRI on 3T MR scanner prior to RT. Thirty-seven men (73%) were treated with external beam RT alone, 12 men (24%) were treated with brachytherapy monotherapy, and two men (4%) were treated with external beam RT with brachytherapy boost. The index lesion was outlined by a radiologist and quantitative apparent diffusion coefficient (ADC), T2 and DCE parameters were measured. Biochemical failure was defined using the Phoenix criteria. RESULTS: After a median follow-up of 65 months, seven patients had biochemical failure. ADC had an area under the receiver operating characteristic curve of 0.71 for predicting RT outcome with significantly lower ADC (0.78 ± 0.17 vs 0.96 ± 0.26 µm2/ms, p = 0.04) of the index lesion in men with biochemical failure. Ideal ADC cutoff point (Youdens index) was 0.96 µm2/ms which had a sensitivity of 100% and specificity of 48% for predicting biochemical failure. Kaplan-Meier analysis showed that lower ADC values were associated with significantly lower freedom from biochemical failure (FFBF, p = 0.03, no failures out of 20 men if ADC ≥ 0.96 µm2/ms; seven of 31 with failures if ADC < 0.96 µm2/ms). On multivariable analysis, ADC was associated with FFBF (HR 0.96 per increase in ADC of 0.01 um2/ms [95% CI, 0.92-1.00]; p = 0.042) after accounting for National Comprehensive Cancer Network risk category (p = 0.064) and receipt of androgen deprivation therapy (p = 0.141). Quantitative T2 and DCE parameters were not associated with biochemical outcome. CONCLUSION: Our results suggest that quantitative ADC values of the index lesion may predict biochemical failure following primary radiotherapy in patients with PCa. Lower ADC values were associated with inferior biochemical control.

Improving Tumor Hypoxia Location in 18F-Misonidazole PET with Dynamic Contrast-enhanced MRI Using Quantitative Electron Paramagnetic Resonance Partial Oxygen Pressure Images.

Purpose: To enhance the spatial accuracy of fluorine 18 (18F) misonidazole (MISO) PET imaging of hypoxia by using dynamic contrast-enhanced (DCE) MR images as a basis for modifying PET images and by using electron paramagnetic resonance (EPR) partial oxygen pressure (pO2) as the reference standard. Materials and Methods: Mice (n = 10) with leg-borne MCa4 mammary carcinomas underwent EPR imaging, T2-weighted and DCE MRI, and 18F-MISO PET/CT. Images were registered to the same space for analysis. The thresholds of hypoxia for PET and EPR images were tumor-to-muscle ratios greater than or equal to 2.2 mm Hg and less than or equal to 14 mm Hg, respectively. The Dice similarity coefficient (DSC) and Hausdorff distance (d H ) were used to quantify the three-dimensional overlap of hypoxia between pO2 EPR and 18F-MISO PET images. A training subset (n = 6) was used to calculate optimal DCE MRI weighting coefficients to relate EPR to the PET signal; the group average weights were then applied to all tumors (from six training mice and four test mice). The DSC and d H were calculated before and after DCE MRI-corrected PET images were obtained to quantify the improvement in overlap with EPR pO2 images for measuring tumor hypoxia. Results: The means and standard deviations of the DSC and d H between hypoxic regions in original PET and EPR images were 0.35 mm ± 0.23 and 5.70 mm ± 1.7, respectively, for images of all 10 mice. After implementing a preliminary DCE MRI correction to PET data, the DSC increased to 0.86 mm ± 0.18 and the d H decreased to 2.29 mm ± 0.70, showing significant improvement (P < .001) for images of all 10 mice. Specifically, for images of the four independent test mice, the DSC improved with correction from 0.19 ± 0.28 to 0.80 ± 0.29 (P = .02), and the d H improved from 6.40 mm ± 2.5 to 1.95 mm ± 0.63 (P = .01). Conclusion: Using EPR information as a reference standard, DCE MRI information can be used to correct 18F-MISO PET information to more accurately reflect areas of hypoxia.Keywords: Animal Studies, Molecular Imaging, Molecular Imaging-Cancer, PET/CT, MR-Dynamic Contrast Enhanced, MR-Imaging, PET/MR, Breast, Oncology, Tumor Mircoenvironment, Electron Paramagnetic ResonanceSupplemental material is available for this article.© RSNA, 2021.

Quick evaluation of lower leg ischemia in patients with peripheral arterial disease by time maximum intensity projection CT angiography: a pilot study.

BACKGROUND: The purpose of this study is to evaluate a new method involving time maximum intensity projection (t-MIP) postprocessed from dynamic computed tomographic angiography (dyn-CTA) in diagnosing peripheral arterial disease (PAD). METHODS: A population of 34 patients with known PAD was examined with a combined CTA protocol consisting of a standard CTA (s-CTA) scan of the lower extremities and a dyn-CTA scan of the calves. For each lower leg, t-MIP images consisting of the MIP0 (sagittal MIP), MIP+θ (45° lateral MIP), and MIP-θ (- 45° lateral MIP) were automatically generated from dyn-CTA. An objective evaluation of the vascular CT attenuation of the best enhancement phase of dyn-CTA and t-MIP was measured; a subjective evaluation of vessel stenosis and occlusion was performed, assigning a score for t-MIP and s-CTA. The CT attenuation of t-MIP and dyn-CTA was compared, as were the runoff scores of t-MIP and s-CTA. RESULTS: The CT attenuation of t-MIP CTA of three vascular segments from 68 lower extremities was higher than that of the best enhancement phase of dyn-CTA and s-CTA, with statistically significant differences at the posterior tibial artery and fibular artery (all p < 0.05). There were strong correlations (r ≥ 0.75, p < 0.05) of the runoff scores between t-MIP and s-CTA. CONCLUSIONS: There is potential clinical applicability of t-MIP in assisting with the diagnosis of lower leg vascular stenosis in dyn-CTA with reliable diagnostic accuracy and convenient immediacy.

Comparison of DCE-MRI of murine model cancers with a low dose and high dose of contrast agent.

There are increasing concerns regarding intracellular accumulation of gadolinium (Gd) after multiple dynamic contrast enhanced (DCE) MRI scans. We investigated whether a low dose (LD) of Gd-based contrast agent is as effective as a high dose (HD) for quantitative analysis of DCE-MRI data, and evaluated the use of a split dose protocol to obtain new diagnostic parameters. Female C3H mice (n = 6) were injected with mammary carcinoma cells in the hind leg. MRI experiments were performed on 9.4 T scanner. DCE-MRI data were acquired with 1.5 s temporal resolution before and after a LD (0.04 mmol/kg), then again after 30 min followed by a HD (0.2 mmol/kg) bolus injection of Omniscan. The standard Tofts model was used to extract physiological parameters (Ktrans and ve) with the arterial input function derived from muscle reference tissue. In addition, an empirical mathematical model was used to characterize maximum contrast agent uptake (A), contrast agent uptake rate (α) and washout rate (ß and γ). There were moderate to strong correlations (r = 0.69-0.97, p < 0001) for parameters Ktrans, ve, A, α and ß from LD versus HD data. On average, tumor parameters obtained from LD data were significantly larger (p < 0.05) than those from HD data. The parameter ratios, Ktrans, ve, A and α calculated from the LD data divided by the HD data, were all significantly larger than 1.0 (p < 0.003) for tumor. T2* changes following contrast agent injection affected parameters calculated from HD data, but this was not the case for LD data. The results suggest that quantitative analysis of LD data may be at least as effective for cancer characterization as quantitative analysis of HD data. In addition, the combination of parameters from two different doses may provide useful diagnostic information.

Signal intensity form of the Tofts model for quantitative analysis of prostate dynamic contrast enhanced MRI data.

The aim of this study is to develop a signal intensity (S(t)) form of the standard Tofts pharmacokinetic model that avoids the need to calculate tissue contrast agent concentration (C(t)) as function of time (t). We refer to this as 'SI-Tofts' model. Physiological parameters (K trans and v e) calculated using the SI-Tofts and standard Tofts models were compared by using simulations and human prostate dynamic contrast enhanced (DCE) MRI data. This approach was also applied to the Patlak model to compare K trans values calculated from C(t) and S(t). Simulations were performed on DCE-MRI data from the quantitative imaging biomarkers alliance to validate SI-Tofts model. In addition, ultrafast DCE-MRI data were acquired from 18 prostate cancer patients on a Philips Achieva 3T-TX scanner. Regions-of-interest (ROIs) for prostate cancer, normal tissue, gluteal muscle, and iliac artery were manually traced. The C(t) was calculated for each ROI using the standard model with measured pre-contrast tissue T 1 values. Both the simulation and clinical results showed strong correlation (r = 0.87-0.99, p < 0.001) for K trans and v e calculated from the SI-Tofts and standard Tofts models. The SI-Tofts model with a correction factor using the T 1 ratio of blood to tissue significantly improved the K trans estimates. The correlation of K trans obtained from the Patlak model with C(t) vs S(t) was also strong (r = 0.95-0.99, p < 0.001). These preliminary results suggest that physiological parameters from DCE-MRI can be reliably estimated from the SI-Tofts model without contrast agent concentration calculation.