An untrained deep learning method for reconstructing dynamic magnetic resonance images from accelerated model-based data

The purpose of this work is to implement physics-based regularization as a stopping condition in tuning an untrained deep neural network for reconstructing MR images from accelerated data. The ConvDecoder neural network was trained with a physics-based regularization term incorporating the spoiled gradient echo equation that describes variable-flip angle (VFA) data. Fully-sampled VFA k-space data were retrospectively accelerated by factors of R={8,12,18,36} and reconstructed with ConvDecoder (CD), ConvDecoder with the proposed regularization (CD+r), locally low-rank (LR) reconstruction, and compressed sensing with L1-wavelet regularization (L1). Final images from CD+r training were evaluated at the \emph{argmin} of the regularization loss; whereas the CD, LR, and L1 reconstructions were chosen optimally based on ground truth data. The performance measures used were the normalized root-mean square error, the concordance correlation coefficient (CCC), and the structural similarity index (SSIM). The CD+r reconstructions, chosen using the stopping condition, yielded SSIMs that were similar to the CD (p=0.47) and LR SSIMs (p=0.95) across R and that were significantly higher than the L1 SSIMs (p=0.04). The CCC values for the CD+r T1 maps across all R and subjects were greater than those corresponding to the L1 (p=0.15) and LR (p=0.13) T1 maps, respectively. For R > 12 (<4.2 minutes scan time), L1 and LR T1 maps exhibit a loss of spatially refined details compared to CD+r. We conclude that the use of an untrained neural network together with a physics-based regularization loss shows promise as a measure for determining the optimal stopping point in training without relying on fully-sampled ground truth data.Comment: 45 pages, 7 figures, 2 Tables, supplementary material included (10 figures, 4 tables

Sustained improvements in MRI outcomes with abatacept following the withdrawal of all treatments in patients with early, progressive rheumatoid arthritis

Objectives: To assess structural damage progression with subcutaneous abatacept (ABA) in the Assessing Very Early Rheumatoid arthritis Treatment (AVERT) trial following abrupt withdrawal of all rheumatoid arthritis (RA) medication in patients achieving Disease Activity Score (DAS)-defined remission or low disease activity. Methods: Patients with early, active RA were randomised to ABA plus methotrexate (ABA/MTX) 125 mg/week, ABA 125 mg/week or MTX for 12 months. All RA treatments were withdrawn after 12 months in patients with DAS28 (C reactive protein (CRP)) <3.2. Adjusted mean changes from baseline in MRI-based synovitis, osteitis and erosion were calculated for the intention-to-treat population. Results: 351 patients were randomised and treated: ABA/MTX (n=119), ABA (n=116) or MTX (n=116). Synovitis and osteitis improved, and progression of erosion was statistically less with ABA/MTX versus MTX at month 12 (−2.35 vs −0.68, −2.58 vs −0.68, 0.19 vs 1.53, respectively; p<0.01 for each) and month 18 (−1.34 vs −0.49 −2.03 vs 0.34, 0.13 vs 2.0, respectively; p<0.01 for erosion); ABA benefits were numerically intermediate to those for ABA/MTX and MTX. Conclusions: Structural benefits with ABA/MTX or ABA may be maintained 6 months after withdrawal of all treatments in patients who have achieved remission or low disease activity

Mucosa-associated lymphoid tissue lymphoma and concurrent adenocarcinoma of the prostate

Primary mucosa-associated lymphoid tissue (MALT) lymphoma of the prostate is a rare disease that characteristically follows an indolent course. It is believed that infection or chronic inflammation may be triggers for malignant transformation in the prostate, but it is of unknown etiology. Reports of MALT lymphomas of the prostate with other concurrent primary prostate cancers are even more limited. We present the unique case of a 67-year-old male with concurrent adenocarcinoma of the prostate and primary MALT lymphoma of the prostate. The patient was treated with standard therapy for prostate adenocarcinoma, which would also treat a primary MALT lymphoma. He has been disease-free for over one year for both his primary malignancies. This case confirms that MALT lymphoma can arise concurrently with adenocarcinoma of the prostate

Chronic Stroke Sensorimotor Impairment Is Related to Smaller Hippocampal Volumes: An ENIGMA Analysis

Background. Persistent sensorimotor impairments after stroke can negatively impact quality of life. The hippocampus is vulnerable to poststroke secondary degeneration and is involved in sensorimotor behavior but has not been widely studied within the context of poststroke upper‐limb sensorimotor impairment. We investigated associations between non‐lesioned hippocampal volume and upper limb sensorimotor impairment in people with chronic stroke, hypothesizing that smaller ipsilesional hippocampal volumes would be associated with greater sensorimotor impairment. Methods and Results. Cross‐sectional T1‐weighted magnetic resonance images of the brain were pooled from 357 participants with chronic stroke from 18 research cohorts of the ENIGMA (Enhancing NeuoImaging Genetics through Meta‐Analysis) Stroke Recovery Working Group. Sensorimotor impairment was estimated from the FMA‐UE (Fugl‐Meyer Assessment of Upper Extremity). Robust mixed‐effects linear models were used to test associations between poststroke sensorimotor impairment and hippocampal volumes (ipsilesional and contralesional separately; Bonferroni‐corrected, P<0.025), controlling for age, sex, lesion volume, and lesioned hemisphere. In exploratory analyses, we tested for a sensorimotor impairment and sex interaction and relationships between lesion volume, sensorimotor damage, and hippocampal volume. Greater sensorimotor impairment was significantly associated with ipsilesional (P=0.005; β=0.16) but not contralesional (P=0.96; β=0.003) hippocampal volume, independent of lesion volume and other covariates (P=0.001; β=0.26). Women showed progressively worsening sensorimotor impairment with smaller ipsilesional (P=0.008; β=−0.26) and contralesional (P=0.006; β=−0.27) hippocampal volumes compared with men. Hippocampal volume was associated with lesion size (P<0.001; β=−0.21) and extent of sensorimotor damage (P=0.003; β=−0.15). Conclusions. The present study identifies novel associations between chronic poststroke sensorimotor impairment and ipsilesional hippocampal volume that are not caused by lesion size and may be stronger in women.S.-L.L. is supported by NIH K01 HD091283; NIH R01 NS115845. A.B. and M.S.K. are supported by National Health and Medical Research Council (NHMRC) GNT1020526, GNT1045617 (A.B.), GNT1094974, and Heart Foundation Future Leader Fellowship 100784 (A.B.). P.M.T. is supported by NIH U54 EB020403. L.A.B. is supported by the Canadian Institutes of Health Research (CIHR). C.M.B. is supported by NIH R21 HD067906. W.D.B. is supported by the Heath Research Council of New Zealand. J.M.C. is supported by NIH R00HD091375. A.B.C. is supported by NIH R01NS076348-01, Hospital Israelita Albert Einstein 2250-14, CNPq/305568/2016-7. A.N.D. is supported by funding provided by the Texas Legislature to the Lone Star Stroke Clinical Trial Network. Its contents are solely the responsibility of the authors and do not necessarily represent the of ficial views of the Government of the United States or the State of Texas. N.E.-B. is supported by Australian Research Council NIH DE180100893. W.F. is sup ported by NIH P20 GM109040. F.G. is supported by Wellcome Trust (093957). B.H. is funded by and NHMRC fellowship (1125054). S.A.K is supported by NIH P20 HD109040. F.B. is supported by Italian Ministry of Health, RC 20, 21. N.S. is supported by NIH R21NS120274. N.J.S. is supported by NIH/National Institute of General Medical Sciences (NIGMS) 2P20GM109040-06, U54-GM104941. S.R.S. is supported by European Research Council (ERC) (NGBMI, 759370). G.S. is supported by Italian Ministry of Health RC 18-19-20-21A. M.T. is sup ported by National Institute of Neurological Disorders and Stroke (NINDS) R01 NS110696. G.T.T. is supported by Temple University sub-award of NIH R24 –NHLBI (Dr Mickey Selzer) Center for Experimental Neurorehabilitation Training. N.J.S. is funded by NIH/National Institute of Child Health and Human Development (NICHD) 1R01HD094731-01A1

Association of Brain Age, Lesion Volume, and Functional Outcome in Patients With Stroke

BACKGROUND AND OBJECTIVES: Functional outcomes after stroke are strongly related to focal injury measures. However, the role of global brain health is less clear. In this study, we examined the impact of brain age, a measure of neurobiological aging derived from whole-brain structural neuroimaging, on poststroke outcomes, with a focus on sensorimotor performance. We hypothesized that more lesion damage would result in older brain age, which would in turn be associated with poorer outcomes. Related, we expected that brain age would mediate the relationship between lesion damage and outcomes. Finally, we hypothesized that structural brain resilience, which we define in the context of stroke as younger brain age given matched lesion damage, would differentiate people with good vs poor outcomes. METHODS: We conducted a cross-sectional observational study using a multisite dataset of 3-dimensional brain structural MRIs and clinical measures from the ENIGMA Stroke Recovery. Brain age was calculated from 77 neuroanatomical features using a ridge regression model trained and validated on 4,314 healthy controls. We performed a 3-step mediation analysis with robust mixed-effects linear regression models to examine relationships between brain age, lesion damage, and stroke outcomes. We used propensity score matching and logistic regression to examine whether brain resilience predicts good vs poor outcomes in patients with matched lesion damage. RESULTS: We examined 963 patients across 38 cohorts. Greater lesion damage was associated with older brain age (β = 0.21; 95% CI 0.04-0.38, DISCUSSION: We provide evidence that younger brain age is associated with superior poststroke outcomes and modifies the impact of focal damage. The inclusion of imaging-based assessments of brain age and brain resilience may improve the prediction of poststroke outcomes compared with focal injury measures alone, opening new possibilities for potential therapeutic targets

Use of Magnetic Resonance Imaging to Support Dose Selection in a Phase II Trial of Baricitinib Combined with Conventional Synthetic Disease-modifying Antirheumatic Drugs in Rheumatoid Arthritis

Objective: Magnetic resonance imaging (MRI) was used in a Phase IIb study (NCT01185353) of baricitinib in patients with RA to support dose selection for the Phase III program. Methods: 301 patients with active RA on stable methotrexate were randomized 2:1:1:1:1 to placebo or once-daily baricitinib (1-, 2-, 4-, or 8-mg) for up to 24 weeks. 154 patients with definitive radiographic erosion had MRI of the hand/wrist at baseline and weeks 12 and 24. Two expert radiologists, blinded to treatment and visit order, scored images for synovitis, osteitis, bone erosion, and cartilage loss. Combined inflammation (osteitis + 3x synovitis score) and total joint damage (erosion + 2.5x cartilage loss score) scores were calculated. Treatment groups were compared using analysis of covariance adjusting for baseline scores. Results: Mean changes from baseline to week 12 for synovitis were -0.10, -1.50, and -1.60 for patients treated with placebo, baricitinib 4-mg, and baricitinib 8-mg, respectively (P=0.003 vs placebo for baricitinib 4- and 8-mg); mean changes for osteitis were 0.00, -3.20, and -2.10 (P=0.001 vs placebo for baricitinib 4-mg and P=0.037 for 8-mg) and mean changes for bone erosion were 0.90, 0.10, and 0.40 (P=0.089 for 4-mg and P=0.275 for 8 mg), respectively in these treatment groups. Conclusion: Using MRI findings in this subgroup of patients suggest suppression of synovitis, osteitis, and combined inflammation by baricitinib 4- and 8-mg, which corroborate previously demonstrated clinical efficacy of baricitinib and increase confidence that baricitinib 4-mg could positively effect reduction of the radiographic progression in Phase III studies

Repeatability and Response to Therapy of Dynamic Contrast-Enhanced Magnetic Resonance Imaging Biomarkers in Rheumatoid Arthritis in a Large Multicentre Trial Setting.

Objectives To determine the repeatability, and response to therapy, of Dynamic Contrast-Enhanced (DCE) MRI biomarkers of synovitis in hand and wrist of Rheumatoid Arthritis (RA) patients, and in particular the performance of the transfer constant Ktrans, in a multicentre trial setting Methods DCE-MRI and RA MRI scoring (RAMRIS) were performed with meticulous standardisation at baseline, 6 and 24 weeks in a sub-study of fostamatinib monotherapy in reducing synovitis compared with placebo or adalimumab. Analysis employed statistical shape modelling to avoid biased regions-of-interest, kinetic modelling and heuristic analyses. Repeatability was also evaluated. Results At early study termination, DCE-MRI data had been acquired from 58 patients in 19 imaging centres. Ktrans intra-subject coefficient of variation (N=14) was 30%. Ktrans change demonstrated inferiority of fostamatinib (N=11) relative to adalimumab (N=10) after 6 weeks (treatment ratio=1.92, p=0.003), and failed to distinguish fostamatinib from placebo (N=10, p=0.79). RAMRIS showed superiority of fostamatinib relative to placebo at 6 weeks (p=0.023), and did not distinguish fostamatinib from adalimumab at either 6 weeks (p=0.175) or 24 weeks (p=0.230). Conclusion This demonstrated repeatability of Ktrans, and its ability to distinguish treatment groups, show that DCE-MRI biomarkers are suitable for use in multicentre RA trials

Association of Modified Rankin Scale With Recovery Phenotypes in Patients With Upper Extremity Weakness After Stroke

Background and objectivesPrecise measurement of outcomes is essential for stroke trials and clinical care. Prior research has highlighted conceptual differences between global outcome measures such as the modified Rankin Scale (mRS) and domain-specific measures (e.g., motor, sensory, language or cognitive function). This study related motor phenotypes to the mRS, specifically aiming to determine whether mRS levels distinguish motor impairment and function phenotypes, and to compare mRS outcomes to meaningful changes in impairment and function from acute to subacute recovery after stroke.MethodsPatients with upper extremity weakness after ischemic stroke were assessed with a battery of impairment and functional measures within the first week and at 90 days after stroke. Impairment and functional outcomes were examined in relation to 90-day mRS scores. Clinically meaningful changes in motor impairment, activities of daily living, and mobility were examined in relation to 90-day mRS score.ResultsIn this cohort of 73 patients with stroke, impairment and functional outcomes were associated with 90-day mRS scores but showed substantial variability within individual mRS levels: within mRS level 2, upper extremity impairment ranged from near hemiplegia (with an upper extremity Fugl-Meyer score 8) to no deficits (upper extremity Fugl-Meyer score 66). Overall, there were few differences in impairment and functional outcomes between adjacent mRS levels. While some outcome measures were significantly different between mRS levels 3 and 4 (Nine-Hole Peg, Leg Motor, gait velocity, Timed Up and Go, NIH Stroke Scale, and Barthel Index), none of the outcome measures differed between mRS levels 1 and 2. Fugl-Meyer and grip strength were not different between any adjacent mRS levels. A substantial number of patients experienced clinically meaningful changes in impairment and function in the first 90 days after stroke but did not achieve good mRS outcome (mRS score ≤ 2).DiscussionThe mRS broadly relates to domain-specific outcomes after stroke, confirming its established value in stroke trials, but it does not precisely distinguish differences in impairment and function, nor does it sufficiently capture meaningful clinical changes across impairment, activities of daily living status, and mobility. These findings underscore the potential utility of incorporating detailed phenotypic measures along with the mRS in future stroke trials

Integrating mechanism-based modeling with biomedical imaging to build practical digital twins for clinical oncology

Digital twins employ mathematical and computational models to virtually represent a physical object (e.g., planes, human organs), predict the behavior of the object, and enable decision-making to optimize the future behavior of the object. While digital twins have been widely used in engineering for decades, their applications to oncology are only just emerging. Due to advances in experimental techniques quantitatively characterizing cancer, as well advances in the mathematical and computational sciences, the notion of building and applying digital twins to understand tumor dynamics and personalize the care of cancer patients has been increasingly appreciated. In this review, we present the opportunities and challenges of applying digital twins in clinical oncology, with a particular focus on integrating medical imaging with mechanism-based, tissue-scale mathematical modeling. Specifically, we first introduce the general digital twin framework and then illustrate existing applications of image-guided digital twins in healthcare. Next, we detail both the imaging and modeling techniques that provide practical opportunities to build patient-specific digital twins for oncology. We then describe the current challenges and limitations in developing image-guided, mechanism-based digital twins for oncology along with potential solutions. We conclude by outlining five fundamental questions that can serve as a roadmap when designing and building a practical digital twin for oncology and attempt to provide answers for a specific application to brain cancer. We hope that this contribution provides motivation for the imaging science, oncology, and computational communities to develop practical digital twin technologies to improve the care of patients battling cancer