Single allele loss-of-function mutations select and sculpt conditional cooperative networks in breast cancer.

The most common events in breast cancer (BC) involve chromosome arm losses and gains. Here we describe identification of 1089 gene-centric common insertion sites (gCIS) from transposon-based screens in 8 mouse models of BC. Some gCIS are driver-specific, others driver non-specific, and still others associated with tumor histology. Processes affected by driver-specific and histology-specific mutations include well-known cancer pathways. Driver non-specific gCIS target the Mediator complex, Ca++ signaling, Cyclin D turnover, RNA-metabolism among other processes. Most gCIS show single allele disruption and many map to genomic regions showing high-frequency hemizygous loss in human BC. Two gCIS, Nf1 and Trps1, show synthetic haploinsufficient tumor suppressor activity. Many gCIS act on the same pathway responsible for tumor initiation, thereby selecting and sculpting just enough and just right signaling. These data highlight ~1000 genes with predicted conditional haploinsufficient tumor suppressor function and the potential to promote chromosome arm loss in BC.

Diagnostic Yield of Incremental Biopsy Cores and Second Lesion Sampling for In-Gantry MRI-Guided Prostate Biopsy.

BACKGROUND. In-gantry MRI-guided biopsy (MRGB) of the prostate has been shown to be more accurate than other targeted prostate biopsy methods. However, the optimal number of cores to obtain during in-gantry MRGB remains undetermined. OBJECTIVE. The purpose of this study was to assess the diagnostic yield of obtaining an incremental number of cores from the primary lesion and of second lesion sampling during in-gantry MRGB of the prostate. METHODS. This retrospective study included 128 men with 163 prostate lesions who underwent in-gantry MRGB between 2016 and 2019. The men had a total of 163 lesions sampled with two or more cores, 121 lesions sampled with three or more cores, and 52 lesions sampled with four or more cores. A total of 40 men underwent sampling of a second lesion. Upgrade on a given core was defined as a greater International Society of Urological Pathology (ISUP) grade group (GG) relative to the previously obtained cores. Clinically significant prostate cancer (csPCa) was defined as ISUP GG 2 or greater. RESULTS. The frequency of any upgrade was 12.9% (21/163) on core 2 versus 10.7% (13/121) on core 3 (p = .29 relative to core 2) and 1.9% (1/52) on core 4 (p = .03 relative to core 3). The frequency of upgrade to csPCa was 7.4% (12/163) on core 2 versus 4.1% (5/121) on core 3 (p = .13 relative to core 2) and 0% (0/52) on core 4 (p = .07 relative to core 3). The frequency of upgrade on core 2 was higher for anterior lesions (p < .001) and lesions with a higher PI-RADS score (p = .007); the frequency of upgrade on core 3 was higher for apical lesions (p = .01) and lesions with a higher PI-RADS score (p = .01). Sampling of a second lesion resulted in an upgrade in a single patient (2.5%; 1/40); both lesions were PI-RADS category 4 and showed csPCa. CONCLUSION. When performing in-gantry MRGB of the prostate, obtaining three cores from the primary lesion is warranted to optimize csPCa diagnosis. Obtaining a fourth core from the primary lesion or sampling a second lesion has very low yield in upgrading cancer diagnoses. CLINICAL IMPACT. To reduce patient discomfort and procedure times, operators may refrain from obtaining more than three cores or second lesion sampling.

Quantifying Perfusion Properties with DCE-MRI Using a Dictionary Matching Approach.

Perfusion properties can be estimated from pharmacokinetic models applied to DCE-MRI data using curve fitting algorithms; however, these suffer from drawbacks including the local minimum problem and substantial computational time. Here, a dictionary matching approach is proposed as an alternative. Curve fitting and dictionary matching were applied to simulated data using the dual-input single-compartment model with known perfusion property values and 5 in vivo DCE-MRI datasets. In simulation at SNR 60 dB, the dictionary estimate had a mean percent error of 0.4-1.0% for arterial fraction, 0.5-1.4% for distribution volume, and 0.0% for mean transit time. The curve fitting estimate had a mean percent error of 1.1-2.1% for arterial fraction, 0.5-1.3% for distribution volume, and 0.2-1.8% for mean transit time. In vivo, dictionary matching and curve fitting showed no statistically significant differences in any of the perfusion property measurements in any of the 10 ROIs between the methods. In vivo, the dictionary method performed over 140-fold faster than curve fitting, obtaining whole volume perfusion maps in just over 10 s. This study establishes the feasibility of using a dictionary matching approach as a new and faster way of estimating perfusion properties from pharmacokinetic models in DCE-MRI.

Single breath-hold 3D cardiac T1 mapping using through-time spiral GRAPPA.

The quantification of cardiac T1 relaxation time holds great potential for the detection of various cardiac diseases. However, as a result of both cardiac and respiratory motion, only one two-dimensional T1 map can be acquired in one breath-hold with most current techniques, which limits its application for whole heart evaluation in routine clinical practice. In this study, an electrocardiogram (ECG)-triggered three-dimensional Look-Locker method was developed for cardiac T1 measurement. Fast three-dimensional data acquisition was achieved with a spoiled gradient-echo sequence in combination with a stack-of-spirals trajectory and through-time non-Cartesian generalized autocalibrating partially parallel acquisition (GRAPPA) acceleration. The effects of different magnetic resonance parameters on T1 quantification with the proposed technique were first examined by simulating data acquisition and T1 map reconstruction using Bloch equation simulations. Accuracy was evaluated in studies with both phantoms and healthy subjects. These results showed that there was close agreement between the proposed technique and the reference method for a large range of T1 values in phantom experiments. In vivo studies further demonstrated that rapid cardiac T1 mapping for 12 three-dimensional partitions (spatial resolution, 2 × 2 × 8 mm3 ) could be achieved in a single breath-hold of ~12 s. The mean T1 values of myocardial tissue and blood obtained from normal volunteers at 3 T were 1311 ± 66 and 1890 ± 159 ms, respectively. In conclusion, a three-dimensional T1 mapping technique was developed using a non-Cartesian parallel imaging method, which enables fast and accurate T1 mapping of cardiac tissues in a single short breath-hold.

Estimation of perfusion properties with MR Fingerprinting Arterial Spin Labeling.

In this study, the acquisition of ASL data and quantification of multiple hemodynamic parameters was explored using a Magnetic Resonance Fingerprinting (MRF) approach. A pseudo-continuous ASL labeling scheme was used with pseudo-randomized timings to acquire the MRF ASL data in a 2.5 min acquisition. A large dictionary of MRF ASL signals was generated by combining a wide range of physical and hemodynamic properties with the pseudo-random MRF ASL sequence and a two-compartment model. The acquired signals were matched to the dictionary to provide simultaneous quantification of cerebral blood flow, tissue time-to-peak, cerebral blood volume, arterial time-to-peak, B1, and T1. A study in seven healthy volunteers resulted in the following values across the population in grey matter (mean ±â€¯standard deviation): cerebral blood flow of 69.1 ±â€¯6.1 ml/min/100 g, arterial time-to-peak of 1.5 ±â€¯0.1 s, tissue time-to-peak of 1.5 ±â€¯0.1 s, T1 of 1634 ms, cerebral blood volume of 0.0048 ±â€¯0.0005. The CBF measurements were compared to standard pCASL CBF estimates using a one-compartment model, and a Bland-Altman analysis showed good agreement with a minor bias. Repeatability was tested in five volunteers in the same exam session, and no statistical difference was seen. In addition to this validation, the MRF ASL acquisition's sensitivity to the physical and physiological parameters of interest was studied numerically.

MR Fingerprinting for Rapid Quantitative Abdominal Imaging.

PURPOSE: To develop a magnetic resonance (MR) "fingerprinting" technique for quantitative abdominal imaging. MATERIALS AND METHODS: This HIPAA-compliant study had institutional review board approval, and informed consent was obtained from all subjects. To achieve accurate quantification in the presence of marked B0 and B1 field inhomogeneities, the MR fingerprinting framework was extended by using a two-dimensional fast imaging with steady-state free precession, or FISP, acquisition and a Bloch-Siegert B1 mapping method. The accuracy of the proposed technique was validated by using agarose phantoms. Quantitative measurements were performed in eight asymptomatic subjects and in six patients with 20 focal liver lesions. A two-tailed Student t test was used to compare the T1 and T2 results in metastatic adenocarcinoma with those in surrounding liver parenchyma and healthy subjects. RESULTS: Phantom experiments showed good agreement with standard methods in T1 and T2 after B1 correction. In vivo studies demonstrated that quantitative T1, T2, and B1 maps can be acquired within a breath hold of approximately 19 seconds. T1 and T2 measurements were compatible with those in the literature. Representative values included the following: liver, 745 msec ± 65 (standard deviation) and 31 msec ± 6; renal medulla, 1702 msec ± 205 and 60 msec ± 21; renal cortex, 1314 msec ± 77 and 47 msec ± 10; spleen, 1232 msec ± 92 and 60 msec ± 19; skeletal muscle, 1100 msec ± 59 and 44 msec ± 9; and fat, 253 msec ± 42 and 77 msec ± 16, respectively. T1 and T2 in metastatic adenocarcinoma were 1673 msec ± 331 and 43 msec ± 13, respectively, significantly different from surrounding liver parenchyma relaxation times of 840 msec ± 113 and 28 msec ± 3 (P < .0001 and P < .01) and those in hepatic parenchyma in healthy volunteers (745 msec ± 65 and 31 msec ± 6, P < .0001 and P = .021, respectively). CONCLUSION: A rapid technique for quantitative abdominal imaging was developed that allows simultaneous quantification of multiple tissue properties within one 19-second breath hold, with measurements comparable to those in published literature.

Multiparametric MR Imaging in Abdominal Malignancies.

Modern MR imaging protocols can yield both anatomic and functional information for the assessment of hepatobiliary and pancreatic malignancies. Diffusion-weighted imaging is fully integrated into state-of-the-art protocols for tumor detection, characterization, and therapy monitoring. Hepatobiliary contrast agents have gained ground in the evaluation of focal liver lesions during the last years. Perfusion MR imaging is expected to have a central role for monitoring therapy in body tumors treated with antivascular drugs. Approaches such as Magnetic resonance (MR) elastography and (1)H-MR spectroscopy are still confined to research centers, but with the potential to grow in a short time frame.

Rapid volumetric T1 mapping of the abdomen using three-dimensional through-time spiral GRAPPA.

PURPOSE: To develop an ultrafast T1 mapping method for high-resolution, volumetric T1 measurements in the abdomen. METHODS: The Look-Locker method was combined with a stack-of-spirals acquisition accelerated using three-dimensional (3D) through-time spiral GRAPPA reconstruction for fast data acquisition. A segmented k-space acquisition scheme was proposed and the time delay between segments for the recovery of longitudinal magnetization was optimized using Bloch equation simulations. The accuracy of this method was validated in a phantom experiment and in vivo T1 measurements were performed with 35 asymptomatic subjects on both 1.5 Tesla (T) and 3T MRI systems. RESULTS: Phantom experiments yielded close agreement between the proposed method and gold standard measurements for a large range of T1 values (200 to 1600 ms). The in vivo results further demonstrate that high-resolution T1 maps (2 × 2 × 4 mm(3)) for 32 slices can be achieved in a single clinically feasible breath-hold of approximately 20 s. The T1 values for multiple organs and tissues in the abdomen are in agreement with the published literature. CONCLUSION: A high-resolution 3D abdominal T1 mapping technique was developed, which allows fast and accurate T1 mapping of multiple abdominal organs and tissues in a single breath-hold.

Ras Signaling Is a Key Determinant for Metastatic Dissemination and Poor Survival of Luminal Breast Cancer Patients.

Breast cancer is associated with alterations in a number of growth factor and hormone-regulated signaling pathways. Mouse models of metastatic breast cancer typically feature mutated oncoproteins that activate PI3K, Stat3, and Ras signaling, but the individual and combined roles of these pathways in breast cancer progression are poorly understood. In this study, we examined the relationship between oncogenic pathway activation and breast cancer subtype by analyzing mouse mammary tumor formation in which each pathway was activated singly or pairwise. All three oncogenes showed cooperation during primary tumor formation, but efficient dissemination was only dependent on Ras. In addition, transcriptional profiling demonstrated that Ras induced adenocarcinomas with molecular characteristics related to human basal-like and HER2(+) tumors. In contrast, Ras combined with PIK3CA(H1047R), an oncogenic mutant linked to ERα(+)/luminal breast cancer in humans, induced metastatic luminal B-like tumors. Consistent with these data, elevated Ras signaling was associated with basal-like and HER2(+) subtype tumors in humans and showed a statistically significant negative association with estrogen receptor (ER) signaling across all breast cancer. Despite this, there are luminal tumors with elevated Ras signaling. Importantly, when considered as a continuous variable, Ras pathway activation was strongly linked to reduced survival of patients with ERα(+) disease independent of PI3K or Stat3 activation. Therefore, our studies suggest that Ras activation is a key determinant for dissemination and poor prognosis of ERα(+)/luminal breast cancer in humans, and hormone therapy supplemented with Ras-targeting agents may be beneficial for treating this aggressive subtype.

Free-breathing liver perfusion imaging using 3-dimensional through-time spiral generalized autocalibrating partially parallel acquisition acceleration.

OBJECTIVES: The goal of this study was to develop free-breathing high-spatiotemporal resolution dynamic contrast-enhanced liver magnetic resonance imaging using non-Cartesian parallel imaging acceleration, and quantitative liver perfusion mapping. MATERIALS AND METHODS: This study was approved by the local institutional review board and written informed consent was obtained from all participants. Ten healthy subjects and 5 patients were scanned on a Siemens 3-T Skyra scanner. A stack-of-spirals trajectory was undersampled in-plane with a reduction factor of 6 and reconstructed using 3-dimensional (3D) through-time non-Cartesian generalized autocalibrating partially parallel acquisition. High-resolution 3D images were acquired with a true temporal resolution of 1.6 to 1.9 seconds while the subjects were breathing freely. A dual-input single-compartment model was used to retrieve liver perfusion parameters from dynamic contrast-enhanced magnetic resonance imaging data, which were coregistered using an algorithm designed to reduce the effects of dynamic contrast changes on registration. Image quality evaluation was performed on spiral images and conventional images from 5 healthy subjects. RESULTS: Images with a spatial resolution of 1.9 × 1.9 × 3 mm3 were obtained with whole-liver coverage. With an imaging speed of better than 2 s/vol, free-breathing scans were achieved and dynamic changes in enhancement were captured. The overall image quality of free-breathing spiral images was slightly lower than that of conventional long breath-hold Cartesian images, but it provided clinically acceptable or better image quality. The free-breathing 3D images were registered with almost no residual motion in liver tissue. After the registration, quantitative whole-liver 3D perfusion maps were obtained and the perfusion parameters are all in good agreement with the literature. CONCLUSIONS: This high-spatiotemporal resolution free-breathing 3D liver imaging technique allows voxelwise quantification of liver perfusion.

STAT3 promotes survival of mutant photoreceptors in inherited photoreceptor degeneration models.

Inherited photoreceptor degenerations (IPDs), a group of incurable progressive blinding diseases, are caused by mutations in more than 200 genes, but little is known about the molecular pathogenesis of photoreceptor (PR) death. Increased retinal expression of STAT3 has been observed in response to many retinal insults, including IPDs, but the role of this increase in PR death is unknown. Here, we show that the expression of Stat3 is increased in PRs of the Tg(RHO P347S) and Prph2(rds) (/+) mouse models of IPD and is activated by tyrosine phosphorylation. PR-specific deletion of Stat3 substantially accelerated PR degeneration in both mutant strains. In contrast, increased PR-specific expression of ROSA26 (R26) alleles encoding either WT STAT3 (Stat3(wt)) or the gain-of-function variant STAT3(C) (Stat3(C)) improved PR survival in both models. Moreover, PR signaling in Tg(RHO P347S) mice carrying either a R26-Stat3(wt) or R26-Stat3(C) allele demonstrated increased a-wave amplitude of the scotopic electroretinogram. Phosphorylation of STAT3 at tyrosine 705 was required for the prosurvival effect because an R26-Stat3(Y705F) allele was not protective. The prosurvival role of enhanced Stat3 activity was validated using recombinant adenoassociated virus (rAAV) vector-mediated PR Stat3 expression in Tg(RHO P347S) mice. Our findings (i) establish that the increase in endogenous PR Stat3 expression is a protective response in IPDs, (ii) suggest that therapeutic augmentation of PR Stat3 expression has potential as a common neuroprotective therapy for these disorders, and (iii) indicate that prosurvival molecules whose expression is increased in mutant PRs may have promise as novel therapies for IPDs.

Quantification of left ventricular functional parameter values using 3D spiral bSSFP and through-time non-Cartesian GRAPPA.

BACKGROUND: The standard clinical acquisition for left ventricular functional parameter analysis with cardiovascular magnetic resonance (CMR) uses a multi-breathhold multi-slice segmented balanced SSFP sequence. Performing multiple long breathholds in quick succession for ventricular coverage in the short-axis orientation can lead to fatigue and is challenging in patients with severe cardiac or respiratory disorders. This study combines the encoding efficiency of a six-fold undersampled 3D stack of spirals balanced SSFP sequence with 3D through-time spiral GRAPPA parallel imaging reconstruction. This 3D spiral method requires only one breathhold to collect the dynamic data. METHODS: Ten healthy volunteers were recruited for imaging at 3 T. The 3D spiral technique was compared against 2D imaging in terms of systolic left ventricular functional parameter values (Bland-Altman plots), total scan time (Welch's t-test) and qualitative image rating scores (Wilcoxon signed-rank test). RESULTS: Systolic left ventricular functional values were not significantly different (i.e. 3D-2D) between the methods. The 95% confidence interval for ejection fraction was -0.1 ± 1.6% (mean ± 1.96*SD). The total scan time for the 3D spiral technique was 48 s, which included one breathhold with an average duration of 14 s for the dynamic scan, plus 34 s to collect the calibration data under free-breathing conditions. The 2D method required an average of 5 min 40s for the same coverage of the left ventricle. The difference between 3D and 2D image rating scores was significantly different from zero (Wilcoxon signed-rank test, p < 0.05); however, the scores were at least 3 (i.e. average) or higher for 3D spiral imaging. CONCLUSION: The 3D through-time spiral GRAPPA method demonstrated equivalent systolic left ventricular functional parameter values, required significantly less total scan time and yielded acceptable image quality with respect to the 2D segmented multi-breathhold standard in this study. Moreover, the 3D spiral technique used just one breathhold for dynamic imaging, which is anticipated to reduce patient fatigue as part of the complete cardiac examination in future studies that include patients.

Quantitative high-resolution renal perfusion imaging using 3-dimensional through-time radial generalized autocalibrating partially parallel acquisition.

OBJECTIVES: Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) examinations of the kidneys provide quantitative information on renal perfusion and filtration. However, these examinations are often difficult to implement because of respiratory motion and their need for a high spatiotemporal resolution and 3-dimensional coverage. Here, we present a free-breathing quantitative renal DCE-MRI examination acquired with a highly accelerated stack-of-stars trajectory and reconstructed with 3-dimensional (3D) through-time radial generalized autocalibrating partially parallel acquisition (GRAPPA), using half and quarter doses of gadolinium contrast. MATERIALS AND METHODS: Data were acquired in 10 asymptomatic volunteers using a stack-of-stars trajectory that was undersampled in-plane by a factor of 12.6 with respect to Nyquist sampling criterion and using partial Fourier of 6/8 in the partition direction. Data had a high temporal (2.1-2.9 seconds per frame) and spatial (approximately 2.2 mm) resolution with full 3D coverage of both kidneys (350-370 mm × 79-92 mm). Images were successfully reconstructed with 3D through-time radial GRAPPA, and interframe respiratory motion was compensated by using an algorithm developed to automatically use images from multiple points of enhancement as references for registration. Quantitative pharmacokinetic analysis was performed using a separable dual-compartment model. RESULTS: Region-of-interest (ROI) pharmacokinetic analysis provided estimates (mean (SD)) of quantitative renal parameters after a half dose: 218.1 (57.1) mL/min per 100 mL; plasma mean transit time, 4.8 (2.2) seconds; renal filtration, 28.7 (10.0) mL/min per 100 mL; and tubular mean transit time, 131.1 (60.2) seconds in 10 kidneys. The ROI pharmacokinetic analysis provided estimates (mean (SD)) of quantitative renal parameters after a quarter dose: 218.1 (57.1) mL/min per 100 mL; plasma mean transit time, 4.8 (2.2) seconds; renal filtration, 28.7 (10.0) mL/min per 100 mL; and tubular mean transit time, 131.1 (60.2) seconds in the 10 kidneys. Three-dimensional pixelwise parameter maps were also evaluated. CONCLUSIONS: Highly undersampled data were successfully reconstructed with 3D through-time radial GRAPPA to achieve a high-resolution 3-dimensional renal DCE-MRI examination. The acquisition was completely free breathing, and the images were registered to compensate for respiratory motion. This allowed for an accurate high-resolution 3D quantitative renal functional mapping of perfusion and filtration parameters.

Non-Cartesian parallel imaging reconstruction.

Non-Cartesian parallel imaging has played an important role in reducing data acquisition time in MRI. The use of non-Cartesian trajectories can enable more efficient coverage of k-space, which can be leveraged to reduce scan times. These trajectories can be undersampled to achieve even faster scan times, but the resulting images may contain aliasing artifacts. Just as Cartesian parallel imaging can be used to reconstruct images from undersampled Cartesian data, non-Cartesian parallel imaging methods can mitigate aliasing artifacts by using additional spatial encoding information in the form of the nonhomogeneous sensitivities of multi-coil phased arrays. This review will begin with an overview of non-Cartesian k-space trajectories and their sampling properties, followed by an in-depth discussion of several selected non-Cartesian parallel imaging algorithms. Three representative non-Cartesian parallel imaging methods will be described, including Conjugate Gradient SENSE (CG SENSE), non-Cartesian generalized autocalibrating partially parallel acquisition (GRAPPA), and Iterative Self-Consistent Parallel Imaging Reconstruction (SPIRiT). After a discussion of these three techniques, several potential promising clinical applications of non-Cartesian parallel imaging will be covered.

Three-dimensional through-time radial GRAPPA for renal MR angiography.

PURPOSE: To achieve high temporal and spatial resolution for contrast-enhanced time-resolved MR angiography exams (trMRAs), fast imaging techniques such as non-Cartesian parallel imaging must be used. In this study, the three-dimensional (3D) through-time radial generalized autocalibrating partially parallel acquisition (GRAPPA) method is used to reconstruct highly accelerated stack-of-stars data for time-resolved renal MRAs. MATERIALS AND METHODS: Through-time radial GRAPPA has been recently introduced as a method for non-Cartesian GRAPPA weight calibration, and a similar concept can also be used in 3D acquisitions. By combining different sources of calibration information, acquisition time can be reduced. Here, different GRAPPA weight calibration schemes are explored in simulation, and the results are applied to reconstruct undersampled stack-of-stars data. RESULTS: Simulations demonstrate that an accurate and efficient approach to 3D calibration is to combine a small number of central partitions with as many temporal repetitions as exam time permits. These findings were used to reconstruct renal trMRA data with an in-plane acceleration factor as high as 12.6 with respect to the Nyquist sampling criterion, where the lowest root mean squared error value of 16.4% was achieved when using a calibration scheme with 8 partitions, 16 repetitions, and a 4 projection × 8 read point segment size. CONCLUSION: 3D through-time radial GRAPPA can be used to successfully reconstruct highly accelerated non-Cartesian data. By using in-plane radial undersampling, a trMRA can be acquired with a temporal footprint less than 4s/frame with a spatial resolution of approximately 1.5 mm × 1.5 mm × 3 mm.

Clinical evaluation of CAIPIRINHA: comparison against a GRAPPA standard.

PURPOSE: To evaluate image quality when using a CAIPIRINHA sampling pattern in comparison to a standard GRAPPA sampling pattern in patients undergoing a routine three-dimensional (3D) breathheld liver exam. CAIPIRINHA uses an optimized phase encoding sampling strategy to alter aliasing artifacts in 3D acquisitions to improve parallel imaging reconstruction. MATERIALS AND METHODS: Twenty patient volunteers were scanned using a 3D VIBE acquisition with an acceleration factor of four using a CAIPIRINHA and standard GRAPPA sampling pattern. CAIPIRINHA and GRAPPA images were evaluated by three radiologists in a two alternative forced choice test, and the Wilcoxon signed rank test was performed. RESULTS: The CAIPIRINHA sampling pattern was preferred in an average of 68% of the comparisons, and the Wilcoxon signed rank test showed a significant improvement in CAIPIRINHA images (P = 0.014). This analysis indicates that in the given sample set, CAIPIRINHA preference over the GRAPPA standard was statistically significant. CONCLUSION: This work shows that for an acceleration factor of four, a CAIPIRINHA accelerated VIBE acquisition provides significantly improved image quality in comparison to the current GRAPPA standard. This allows a further reduction in imaging time for similar spatial resolutions, which can reduce long breathhold requirements in abdominal imaging, and may be particularly helpful in patients who cannot provide requisite breathholds with current protocols.

Simultaneous magnetic resonance angiography and perfusion (MRAP) measurement: initial application in lower extremity skeletal muscle.

PURPOSE: To obtain a simultaneous 3D magnetic resonance angiography and perfusion (MRAP) using a single acquisition and to demonstrate MRAP in the lower extremities. A time-resolved contrast-enhanced exam was used in MRAP to simultaneously acquire a contrast-enhanced MR angiography (MRA) and dynamic contrast-enhanced (DCE) perfusion, which currently requires separate acquisitions and thus two contrast doses. MRAP can be used to assess large and small vessels in vascular pathologies such as peripheral arterial disease. MATERIALS AND METHODS: MRAP was performed on 10 volunteers following unilateral plantar flexion exercise (one leg exercised and one rested) on two separate days. Data were acquired after administration of a single dose of contrast agent using an optimized sampling strategy, parallel imaging, and partial-Fourier acquisition to obtain a high spatial resolution, 3D-MRAP frame every 4 seconds. Two radiologists assessed MRAs for image quality, a signal-to-noise ratio (SNR) analysis was performed, and pharmacokinetic modeling yielded perfusion (K(trans) ). RESULTS: MRA images had high SNR and radiologist-assessed diagnostic quality. Mean K(trans) ± standard error were 0.136 ± 0.009, 0.146 ± 0.012, and 0.191 ± 0.012 min(-1) in the resting tibialis anterior, gastrocnemius, and soleus, respectively, which significantly increased with exercise to 0.291 ± 0.018, 0.270 ± 0.019, and 0.338 ± 0.022 min(-1) . Bland-Altman analysis showed good repeatability. CONCLUSION: MRAP provides simultaneous high-resolution MRA and quantitative DCE exams to assess large and small vessels with a single contrast dose. Application in skeletal muscle shows quantitative, repeatable perfusion measurements, and the ability to measure physiological differences.

Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation.

PIK3CA, which codes for the p110α catalytic subunit of phosphatidylinositol 3-kinase, is one of the most frequently mutated genes in human breast cancer. Here, we describe a mouse model for PIK3CA-induced breast cancer by using the ROSA26 (R26) knock-in system, in which targeted Pik3ca alleles can be activated through transgenic expression of Cre recombinase. We mated Pik3ca(H1047R) and Pik3ca(wt) knock-in lines with MMTV-Cre transgenics, which express Cre in mammary epithelium. Starting at approximately 5 months of age, female R26-Pik3ca(H1047R);MMTV-Cre mice, but not control R26-Pik3ca(wt);MMTV-Cre mice, developed mammary tumors, as well as lymphoid and skin malignancies. R26-Pik3ca(H1047R);MMTV-Cre mammary tumors were typically either adenosquamous carcinoma or adenomyoepithelioma. As p53 is the most commonly mutated gene in breast cancer, we tested for genetic interaction between Pik3ca(H1047R) and p53 loss-of-function mutations in R26-Pik3ca(H1047R);p53(loxP/+);MMTV-Cre mice. This led to decreased survival of double-mutant animals, which developed lymphoma and mammary tumors with rapid kinetics. Mammary tumors that formed in p53(loxP/+);MMTV-Cre conditional mutants were either poorly differentiated adenocarcinoma or spindle cell/EMT, whereas R26-Pik3ca(H1047R);p53(loxP/+);MMTV-Cre mammary tumors were mostly adenosquamous carcinoma or spindle cell/EMT indicating that double-mutant mice develop a distinct spectrum of mammary tumors. Thus, an oncogenic variant of PIK3CA implicated in multiple human breast cancer subtypes can induce a very diverse spectrum of mammary tumors in mice. Furthermore, Pik3ca(H1047R) shows cooperation with p53, which altered the specific tumors that formed. Thus, the two most frequently mutated genes in human breast cancer show cooperation in mammary tumor formation.