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Neuromuscular diseases are characterized by progressive muscle degeneration and muscle weakness resulting in functional disabilities. While each of these diseases is individually rare, they are common as a group, and a large majority lacks effective treatment with fully market approved drugs. Magnetic resonance imaging and spectroscopy techniques (MRI and MRS) are showing increasing promise as an outcome measure in clinical trials for these diseases. In 2013, the European Union funded the COST (co-operation in science and technology) action BM1304 called MYO-MRI (www.myo-mri.eu), with the overall aim to advance novel MRI and MRS techniques for both diagnosis and quantitative monitoring of neuromuscular diseases through sharing of expertise and data, joint development of protocols, opportunities for young researchers and creation of an online atlas of muscle MRI and MRS. In this report, the topics that were discussed in the framework of working group 3, which had the objective to: Explore new contrasts, new targets and new imaging techniques for NMD are described. The report is written by the scientists who attended the meetings and presented their data. An overview is given on the different contrasts that MRI can generate and their application, clinical needs and desired readouts, and emerging methods.

PURPOSE - Functional magnetic resonance imaging with BOLD contrast is widely used for detecting brain activity in the cortex. Recently, several studies have described anisotropic correlations of resting-state BOLD signals between voxels in white matter (WM). These local WM correlations have been modeled as functional-correlation tensors, are largely consistent with underlying WM fiber orientations derived from diffusion MRI, and appear to change during functional activity. However, functional-correlation tensors have several limitations. The use of only nearest-neighbor voxels makes functional-correlation tensors sensitive to noise. Furthermore, adjacent voxels tend to have higher correlations than diagonal voxels, resulting in orientation-related biases. Finally, the tensor model restricts functional correlations to an ellipsoidal bipolar-symmetric shape, and precludes the ability to detect complex functional orientation distributions (FODs).
METHODS - We introduce high-angular-resolution functional-correlation imaging (HARFI) to address these limitations. In the same way that high-angular-resolution diffusion imaging (HARDI) techniques provide more information than diffusion tensors, we show that the HARFI model is capable of characterizing complex FODs expected to be present in WM.
RESULTS - We demonstrate that the unique radial and angular sampling strategy eliminates orientation biases present in tensor models. We further show that HARFI FODs are able to reconstruct known WM pathways. Finally, we show that HARFI allows asymmetric "bending" and "fanning" distributions, and propose asymmetric and functional indices which may increase fiber tracking specificity, or highlight boundaries between functional regions.
CONCLUSIONS - The results suggest the HARFI model could be a robust, new way to evaluate anisotropic BOLD signal changes in WM.
© 2018 International Society for Magnetic Resonance in Medicine.

Novel near-infrared contrast agents based on the quaterrylene structure were strategically developed and tested for high photo-stability. Both a dendrimeric quaterrylene molecule, QR-G2-COOH, and a small molecule cationic quaterrylene dye, QR-4PyC4, remain optically stable and continue to generate a competitive photoacoustic response when irradiated by short near-infrared laser pulses for a relatively long time in an in-vitro cell study, unlike indocyanine green that rapidly decreases photoacoustic signal amplitude. The small molecule dye, QR-4PyC4 exhibits not only significantly higher cellular uptake rate than QR-G2-COOH and indocyanine green, but also low toxicity at a concentration of up to 10 μM. The dendrimeric dye, QR-G2-COOH that has surface functional groups available for conjugation with targeting and therapeutic agents shows the highest photoacoustic amplitude with high optical stability. Therefore, QR-4PyC4 can be a promising universal, sensitive and reliable photoacoustic contrast agent and QR-G2-COOH has great potential as a nano-platform with stable photoacoustic imaging capability.
Copyright © 2018 Elsevier B.V. All rights reserved.

OBJECTIVE - To assess drug reactions (ADRs) encountered by practicing urologists for contrast instilled into the urinary collecting system, and to describe current practice patterns regarding contrast administration into the urinary tract for patients with known contrast allergies.
METHODS - Endourological Society members were e-mailed a web-based survey about their prior experience with contrast-related ADRs and practices for contrast administration into the urinary tract among patients with known intravenous contrast allergies. Chi-squared analysis was used to compare management patterns between patients with established allergies and those without.
RESULTS - An estimated 2300-2500 e-mails were reached, resulting in an estimated response rate of 6.3%-8%. Over 75% of respondents were fellowship trained. Average time in practice was 16 years, and respondents performed a mean of 6.7 urologic contrast studies per week. Among respondents, 32.6%, 14.7%, and 4.0% had treated at least 1 patient with a mild, moderate, or severe reaction, respectively. Contrast-related ADRs were most commonly associated with retrograde pyelogram (50%). For patients with known contrast allergies, 5.4% pursue additional work-up before administering contrast in the urinary tract. Pretreatment with antihistamine or steroids is used by 24.8% and 23.4%, respectively. When performing retrograde pyelograms for such patients, urologists are more likely to use dilute contrast (P = .003), but otherwise do not significantly alter technique.
CONCLUSION - Contrast ADRs are encountered not infrequently among practicing urologists. There is notable practice variation in the management of patients with known contrast allergies, though the overall perceived risk of contrast use in these patients is low, provided good technique is used.
Copyright © 2018 Elsevier Inc. All rights reserved.

AIM - To identify combined positron-emission tomography (PET)/magnetic resonance imaging (MRI)-based radiomics as a surrogate biomarker of intratumour disease risk for molecular subtype ccA and ccB in patients with primary clear cell renal cell carcinoma (ccRCC).
MATERIALS AND METHODS - PET/MRI data were analysed retrospectively from eight patients. One hundred and sixty-eight radiomics features for each tumour sampling based on the regionally sampled tumours with 23 specimens were extracted. Sparse partial least squares discriminant analysis (SPLS-DA) was applied to feature screening on high-throughput radiomics features and project the selected features to low-dimensional intrinsic latent components as radiomics signatures. In addition, multilevel omics datasets were leveraged to explore the complementing information and elevate the discriminative ability.
RESULTS - The correct classification rate (CCR) for molecular subtype classification by SPLS-DA using only radiomics features was 86.96% with permutation test p=7×10. When multi-omics datasets including mRNA, microvascular density, and clinical parameters from each specimen were combined with radiomics features to refine the model of SPLS-DA, the best CCR was 95.65% with permutation test, p<10; however, even in the case of generating the classification based on transcription features, which is the reference standard, there is roughly 10% classification ambiguity. Thus, this classification level (86.96-95.65%) of the proposed method represents the discriminating level that is consistent with reality.
CONCLUSION - Featured with high accuracy, an integrated multi-omics model of PET/MRI-based radiomics could be the first non-invasive investigation for disease risk stratification and guidance of treatment in patients with primary ccRCC.
Published by Elsevier Ltd.

PURPOSE - To develop and investigate a set of biophysical models based on a mechanically coupled reaction-diffusion model of the spatiotemporal evolution of tumor growth after radiation therapy.
METHODS AND MATERIALS - Post-radiation therapy response is modeled using a cell death model (M), a reduced proliferation rate model (M), and cell death and reduced proliferation model (M). To evaluate each model, rats (n = 12) with C6 gliomas were imaged with diffusion-weighted magnetic resonance imaging (MRI) and contrast-enhanced MRI at 7 time points over 2 weeks. Rats received either 20 or 40 Gy between the third and fourth imaging time point. Diffusion-weighted MRI was used to estimate tumor cell number within enhancing regions in contrast-enhanced MRI data. Each model was fit to the spatiotemporal evolution of tumor cell number from time point 1 to time point 5 to estimate model parameters. The estimated model parameters were then used to predict tumor growth at the final 2 imaging time points. The model prediction was evaluated by calculating the error in tumor volume estimates, average surface distance, and voxel-based cell number.
RESULTS - For both the rats treated with either 20 or 40 Gy, significantly lower error in tumor volume, average surface distance, and voxel-based cell number was observed for the M and M models compared with the M model. The M model fit, however, had significantly lower sum squared error compared with the M and M models.
CONCLUSIONS - The results of this study indicate that for both doses, the M and M models result in accurate predictions of tumor growth, whereas the M model poorly describes response to radiation therapy.
Copyright © 2017 Elsevier Inc. All rights reserved.

Metastatic clear-cell renal cell carcinoma (ccRCC) affects thousands of patients worldwide each year. Antiangiogenic therapy has been shown to have beneficial effects initially, but resistance is eventually developed. Therefore, it is important to accurately track the response of cancer to different therapeutics in order to appropriately adjust the therapy to maximize efficacy. Change in tumor volume is the current gold standard for determining efficacy of treatment. However, functional variations can occur much earlier than measurable volume changes. Contrast-enhanced ultrasound (CEUS) is an important tool for assessing tumor progression and response to therapy, since it can monitor functional changes in the physiology. In this study, we demonstrate how ultrasound molecular imaging (USMI) can accurately track the evolution of the disease and molecular response to treatment. A cohort of NSG (NOD/scid/gamma) mice was injected with ccRCC cells and treated with either the VEGF inhibitor SU (Sunitinib malate, Selleckchem, TX, USA) or the Notch pathway inhibitor GSI (Gamma secretase inhibitor, PF-03084014, Pfizer, New York, NY, USA), or started on SU and later switched to GSI (Switch group). The therapies used in the study focus on disrupting angiogenesis and proper vessel development. SU inhibits signaling of vascular endothelial growth factor (VEGF), which is responsible for the sprouting of new vasculature, and GSI inhibits the Notch pathway, which is a key factor in the correct maturation of newly formed vasculature. Microbubble contrast agents targeted to VEGFR-2 (VEGF Receptor) were delivered as a bolus, and the bound agents were imaged in 3D after the free-flowing contrast was cleared from the body. Additionally, the tumors were harvested at the end of the study and stained for CD31. The results show that MI can detect changes in VEGFR-2 expression in the group treated with SU within a week of the start of treatment, while differences in volume only become apparent after the mice have been treated for three weeks. Furthermore, USMI can detect response to therapy in 92% of cases after 1 week of treatment, while the detection rate is only 40% for volume measurements. The amount of targeting for the GSI and Control groups was high throughout the duration of the study, while that of the SU and Switch groups remained low. However, the amount of targeting in the Switch group increased to levels similar to those of the Control group after the treatment was switched to GSI. CD31 staining indicates significantly lower levels of patent vasculature for the SU group compared to the Control and GSI groups. Therefore, the results parallel the expected physiological changes in the tumor, since GSI promotes angiogenesis through the VEGF pathway, while SU inhibits it. This study demonstrates that MI can track disease progression and assess functional changes in tumors before changes in volume are apparent, and thus, CEUS can be a valuable tool for assessing response to therapy in disease. Future work is required to determine whether levels of VEGFR-2 targeting correlate with eventual survival outcomes.

Optical coherence tomography (OCT) has become a standard-of-care in retinal imaging. OCT allows non-invasive imaging of the tissue structure but lacks specificity to contrast agents that could be used for in vivo molecular imaging. Photothermal OCT (PT-OCT) is a functional OCT-based technique that has been developed to detect absorbers in a sample. We demonstrate in vivo PT-OCT in the eye for the first time on both endogenous (melanin) and exogenous (gold nanorods) absorbers. Pigmented mice and albino mice (n = 6 eyes) were used to isolate the photothermal signal from the melanin in the retina. Pigmented mice with laser-induced choroidal neovascularization lesions (n = 7 eyes) were also imaged after a systemic injection of gold nanorods to observe their passive accumulation in the retina. This experiment demonstrates the feasibility of PT-OCT to image the distribution of both endogenous and exogenous absorbers in the mouse retina.

BACKGROUND - Patients with chronic kidney disease are at increased risk of cystic kidney disease that requires imaging monitoring in many cases. However, these same patients often have contraindications to contrast-enhanced computed tomography and magnetic resonance imaging. This study evaluates the accuracy of contrast-enhanced ultrasound (CEUS), which is safe for patients with chronic kidney disease, for the characterization of kidney lesions in patients with and without chronic kidney disease.
METHODS - We performed CEUS on 44 patients, both with and without chronic kidney disease, with indeterminate or suspicious kidney lesions (both cystic and solid). Two masked radiologists categorized lesions using CEUS images according to contrast-enhanced ultrasound adapted criteria. CEUS designation was compared to histology or follow-up imaging in cases without available tissue in all patients and the subset with chronic kidney disease to determine sensitivity, specificity and overall accuracy.
RESULTS - Across all patients, CEUS had a sensitivity of 96% (95% CI: 84%, 99%) and specificity of 50% (95% CI: 32%, 68%) for detecting malignancy. Among patients with chronic kidney disease, CEUS sensitivity was 90% (95% CI: 56%, 98%), and specificity was 55% (95% CI: 36%, 73%).
CONCLUSIONS - CEUS has high sensitivity for identifying malignancy of kidney lesions. However, because specificity is low, modifications to the classification scheme for contrast-enhanced ultrasound could be considered as a way to improve contrast-enhanced ultrasound specificity and thus overall performance. Due to its sensitivity, among patients with chronic kidney disease or other contrast contraindications, CEUS has potential as an imaging test to rule out malignancy.
TRIAL REGISTRATION - This trial was registered in clinicaltrials.gov, NCT01751529 .