DCE-Qnet: Deep Network Quantification of Dynamic Contrast Enhanced (DCE) MRI.

Introduction: Quantification of dynamic contrast-enhanced (DCE)-MRI has the potential to provide valuable clinical information, but robust pharmacokinetic modeling remains a challenge for clinical adoption. Methods: A 7-layer neural network called DCE-Qnet was trained on simulated DCE-MRI signals derived from the Extended Tofts model with the Parker arterial input function. Network training incorporated B1 inhomogeneities to estimate perfusion (Ktrans, vp, ve), tissue T1 relaxation, proton density and bolus arrival time (BAT). The accuracy was tested in a digital phantom in comparison to a conventional nonlinear least-squares fitting (NLSQ). In vivo testing was conducted in 10 healthy subjects. Regions of interest in the cervix and uterine myometrium were used to calculate the inter-subject variability. The clinical utility was demonstrated on a cervical cancer patient. Test-retest experiments were used to assess reproducibility of the parameter maps in the tumor. Results: The DCE-Qnet reconstruction outperformed NLSQ in the phantom. The coefficient of variation (CV) in the healthy cervix varied between 5-51% depending on the parameter. Parameter values in the tumor agreed with previous studies despite differences in methodology. The CV in the tumor varied between 1-47%. Conclusion: The proposed approach provides comprehensive DCE-MRI quantification from a single acquisition. DCE-Qnet eliminates the need for separate T1 scan or BAT processing, leading to a reduction of 10 minutes per scan and more accurate quantification.

Rapid P-TEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy.

Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. P-TEFb-mediated pause-release of RNA polymerase II (Pol II) is a conserved regulatory mechanism for synchronous transcriptional induction in response to heat shock, but this pro-survival role has not been examined in the applied context of cancer therapy. Using model systems of pediatric high-grade glioma, we show that rapid genome-wide reorganization of active chromatin facilitates P-TEFb-mediated nascent transcriptional induction within hours of exposure to therapeutic ionizing radiation. Concurrent inhibition of P-TEFb disrupts this chromatin reorganization and blunts transcriptional induction, abrogating key adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival. These studies reveal a central role for P-TEFb underpinning the early adaptive response to radiotherapy, opening avenues for combinatorial treatment in these lethal malignancies.

Development of Chromosome 1q+ Specific Treatment for Highest Risk Pediatric Posterior Fossa Ependymoma.

PURPOSE: There are no effective treatment strategies for children with highest-risk posterior fossa group A ependymoma (PFA). Chromosome 1q gains (1q+) are present in approximately 25% of newly diagnosed PFA tumors, and this number doubles at recurrence. Seventy percent of children with chromosome 1q+ PFA will die because of the tumor, highlighting the urgent need to develop new therapeutic strategies for this population. EXPERIMENTAL DESIGN: In this study, we utilize 1q+ PFA in vitro and in vivo models to test the efficacy of combination radiation and chemotherapy in a preclinical setting. RESULTS: 5-fluorouracil (5FU) enhances radiotherapy in 1q+ PFA cell lines. Specifically, 5FU increases p53 activity mediated by the extra copy of UCK2 located on chromosome 1q in 1q+ PFA. Experimental downregulation of UCK2 resulted in decreased 5FU sensitivity in 1q+ PFA cells. In in vitro studies, a combination of 5FU, retinoid tretinoin (ATRA), and radiation provided the greatest reduction in cellular proliferation and greatest increase in markers of apoptosis in 1q+ PFA cell lines compared with other treatment arms. Similarly, in vivo experiments demonstrated significant enhancement of survival in mice treated with combination radiation and 5FU and ATRA. CONCLUSIONS: These results are the first to identify a chromosome 1q+ specific therapy approach in 1q+ PFA. Existing phase I studies have already established single-agent pediatric safety and dosages of 5FU and ATRA, allowing for expedited clinical application as phase II trials for children with high-risk PFA.

Cross correlation-based misregistration correction for super resolution T2 -weighted spin-echo images: application to prostate.

PURPOSE: The purpose is to develop a retrospective correction for subtle slice-to-slice positional inconsistencies that can occur when overlapped slices are acquired for super resolution in T2 -weighted spin-echo multislice imaging. METHODS: Spin-echo acquisition of overlapped slices is typically done using multiple passes. After the passes are assembled into the final slice set, consecutive slices are correlated due to their overlap. Cross correlation was used to measure slice-to-slice displacement. After Z-dependent filtering to preserve true object shape, the displacements were used to correct slice position. The method was tested in a phantom moved slowly (0.16-0.63 mm/pass) under computer control and in vivo in 16 patients having prostate MRI. RESULTS: Over the motion range, the correlation method had an accuracy within 0.03 mm/pass and precision ± 0.20 mm (ie, subpixel). Corrected images visually resemble the true object. Over the patient studies, the mean range of motion in the anterior-posterior direction was 1.63 mm. Motion-corrected axial images and the sagittal reformats were evaluated as significantly superior over those formed without motion correction. CONCLUSION: The retrospective correlation-based motion-correction method provides significant improvement in the slice-to-slice registration necessary for effective super resolution using overlapped slices.

Modified acquisition strategy for reduced motion artifact in super resolution T2 FSE multislice MRI: Application to prostate.

PURPOSE: To reduce slice-to-slice motion effects in multislice T2 -weighted fast-spin-echo ( T2 FSE) imaging, manifest as "scalloping" in reformats, by modification of the acquisition strategy and to show applicability in prostate MRI. METHODS: T2 FSE images of contiguous or overlapping slices are typically acquired using multiple passes in which each pass is comprised of multiple slices with slice-to-slice gaps. Combination of slices from all passes provides the desired sampling. For enhancement of through-plane resolution with super resolution or for reformatting into other orientations, subtle ≈1 mm motion between passes can cause objectionable "scalloping" artifact. Here we address this by subdivision of each pass into multiple segments. Interleaving of segments from the multiple passes causes all slices to be acquired over substantially the same time, reducing pass-to-pass motion effects. This was implemented in acquiring 78 overlapped T2 FSE axial slices and studied in phantoms and in 14 prostate MRI patients. Super-resolution axial images and sagittal reformats from the original and new segmented acquisitions were evaluated by 3 uroradiologists. RESULTS: For all criteria of sagittal reformats, the segmented acquisition was statistically superior to the original. For all sharpness criteria of axial images, although the trend preferred the original acquisition, the difference was not significant. For artifact in axial images, the segmented acquisition was significantly superior. CONCLUSIONS: For prostate MRI the new segmented acquisition significantly reduces the scalloping motion artifact that can be present in reformats due to long time lags between the acquisition of adjacent or overlapped slices while retaining image sharpness in the acquired axial slices.

Use of kZ -space for high through-plane resolution in multislice MRI: Application to prostate.

PURPOSE: The goal of this work is to demonstrate 1 mm through-plane resolution in multislice T2SE MRI using k Z -space processing of overlapping slices and show applicability in prostate MRI. METHODS: Multiple overlapped slices are acquired and Fourier transformed in the slice-select direction. The slice profile is incorporated into a Tikhonov-regularized reconstruction. Through-plane resolution is tested in a resolution phantom. An anthropomorphic prostate phantom is used to study the SNR, and results are compared with theoretical prediction. The proposed method is tested in 16 patients indicated for clinical prostate MRI who gave written informed consent as overseen by our IRB. The "proposed" vs. "reference" multislice images are compared using multiple evaluation criteria for through-plane resolution. RESULTS: The modulation transfer function (MTF) plots of the resolution phantom show good modulation at frequency 0.5 lp/mm, demonstrating 1 mm through-plane resolution restoration. The SNR measurements experimentally match the theoretically predicted values. The radiological evaluation shows that the proposed method is superior to the reference method for five criteria of sharpness but inferior with respect to artifacts. CONCLUSIONS: In conjunction with overlapped slices a k Z -space-based reconstruction approach can be used to improve through-plane resolution in multislice T2SE MRI. 1 mm resolution is demonstrated from 3.2 mm thick slices. The in vivo results from prostate MRI show improved sharpness when compared to the standard multislice method.

Soft Tissue Sarcoma Stiffness and Perfusion Evaluation by MRE and DCE-MRI for Radiation Therapy Response Assessment: A Technical Feasibility Study.

Soft tissue sarcomas are a rare and heterogeneous group of malignancies that present significant diagnostic and therapeutic challenges. Patient stratification based on tumor aggressiveness and early therapeutic response based on quantitative imaging may improve prediction of treatment response and the evaluation of new treatment strategies in clinical trials. The purpose of this pilot study was to determine the technical feasibility of magnetic resonance elastography (MRE) and dynamic contrast-enhanced (DCE) MRI for the evaluation of sarcoma stiffness and perfusion in 9 patients with histologically confirmed sarcoma. Additionally, we assessed the feasibility of utilizing MRE and DCE-MRI for the early evaluation of response to radiation therapy in 4 patients to determine the utility of further evaluation in a larger cohort study. Tumor size, stiffness, and perfusion parameters all decreased from baseline at the time of the pre-surgery or follow-up MRI, and results were compared to pathology or conventional imaging. MRE and DCE-MRI may be useful for the quantitative evaluation of tumor stiffness and perfusion, and therapy response assessment in soft tissue sarcomas.

Robust and efficient pharmacokinetic parameter non-linear least squares estimation for dynamic contrast enhanced MRI of the prostate.

PURPOSE: To describe an efficient numerical optimization technique using non-linear least squares to estimate perfusion parameters for the Tofts and extended Tofts models from dynamic contrast enhanced (DCE) MRI data and apply the technique to prostate cancer. METHODS: Parameters were estimated by fitting the two Tofts-based perfusion models to the acquired data via non-linear least squares. We apply Variable Projection (VP) to convert the fitting problem from a multi-dimensional to a one-dimensional line search to improve computational efficiency and robustness. Using simulation and DCE-MRI studies in twenty patients with suspected prostate cancer, the VP-based solver was compared against the traditional Levenberg-Marquardt (LM) strategy for accuracy, noise amplification, robustness to converge, and computation time. RESULTS: The simulation demonstrated that VP and LM were both accurate in that the medians closely matched assumed values across typical signal to noise ratio (SNR) levels for both Tofts models. VP and LM showed similar noise sensitivity. Studies using the patient data showed that the VP method reliably converged and matched results from LM with approximate 3× and 2× reductions in computation time for the standard (two-parameter) and extended (three-parameter) Tofts models. While LM failed to converge in 14% of the patient data, VP converged in the ideal 100%. CONCLUSION: The VP-based method for non-linear least squares estimation of perfusion parameters for prostate MRI is equivalent in accuracy and robustness to noise, while being more reliably (100%) convergent and computationally about 3× (TM) and 2× (ETM) faster than the LM-based method.