Magnetic resonance imaging-based bone imaging of the lower limb: Strategies for generating high-resolution synthetic computed tomography.

This study aims at assessing approaches for generating high-resolution magnetic resonance imaging- (MRI-) based synthetic computed tomography (sCT) images suitable for orthopedic care using a deep learning model trained on low-resolution computed tomography (CT) data. To that end, paired MRI and CT data of three anatomical regions were used: high-resolution knee and ankle data, and low-resolution hip data. Four experiments were conducted to investigate the impact of low-resolution training CT data on sCT generation and to find ways to train models on low-resolution data while providing high-resolution sCT images. Experiments included resampling of the training data or augmentation of the low-resolution data with high-resolution data. Training sCT generation models using low-resolution CT data resulted in blurry sCT images. By resampling the MRI/CT pairs before the training, models generated sharper images, presumably through an increase in the MRI/CT mutual information. Alternatively, augmenting the low-resolution with high-resolution data improved sCT in terms of mean absolute error proportionally to the amount of high-resolution data. Overall, the morphological accuracy was satisfactory as assessed by an average intermodal distance between joint centers ranging from 0.7 to 1.2 mm and by an average intermodal root-mean-squared distances between bone surfaces under 0.7 mm. Average dice scores ranged from 79.8% to 87.3% for bony structures. To conclude, this paper proposed approaches to generate high-resolution sCT suitable for orthopedic care using low-resolution data. This can generalize the use of sCT for imaging the musculoskeletal system, paving the way for an MR-only imaging with simplified logistics and no ionizing radiation.

MRI-based synthetic CT in the detection of knee osteoarthritis: Comparison with CT.

Magnetic resonance Imaging is the gold standard for assessment of soft tissues; however, X-ray-based techniques are required for evaluating bone-related pathologies. This study evaluated the performance of synthetic computed tomography (sCT), a novel MRI-based bone visualization technique, compared with CT, for the scoring of knee osteoarthritis. sCT images were generated from the 3T T1-weighted gradient-echo MR images using a trained machine learning algorithm. Two readers scored the severity of osteoarthritis in tibiofemoral and patellofemoral joints according to OACT, which enables the evaluation of osteoarthritis, from its characteristics of joint space narrowing, osteophytes, cysts and sclerosis in CT (and sCT) images. Cohen's κ was used to assess the interreader agreement for each modality, and intermodality agreement of CT- and sCT-based scores for each reader. We also compared the confidence level of readers for grading CT and sCT images using confidence scores collected during grading. Inter-reader agreement for tibiofemoral and patellofemoral joints were almost-perfect for both modalities (κ = 0.83-0.88). The intermodality agreement of osteoarthritis scores between CT and sCT was substantial to almost-perfect for tibiofemoral (κ = 0.63 and 0.84 for the two readers) and patellofemoral joints (κ = 0.78 and 0.81 for the two readers). The analysis of diagnosis confidence scores showed comparable visual quality of the two modalities, where both are showing acceptable confidence levels for scoring OA. In conclusion, in this single-center study, sCT and CT were comparable for the scoring of knee OA.

Synthetic CT for the planning of MR-HIFU treatment of bone metastases in pelvic and femoral bones: a feasibility study.

OBJECTIVES: Visualization of the bone distribution is an important prerequisite for MRI-guided high-intensity focused ultrasound (MRI-HIFU) treatment planning of bone metastases. In this context, we evaluated MRI-based synthetic CT (sCT) imaging for the visualization of cortical bone. METHODS: MR and CT images of nine patients with pelvic and femoral metastases were retrospectively analyzed in this study. The metastatic lesions were osteolytic, osteoblastic or mixed. sCT were generated from pre-treatment or treatment MR images using a UNet-like neural network. sCT was qualitatively and quantitatively compared to CT in the bone (pelvis or femur) containing the metastasis and in a region of interest placed on the metastasis itself, through mean absolute difference (MAD), mean difference (MD), Dice similarity coefficient (DSC), and root mean square surface distance (RMSD). RESULTS: The dataset consisted of 3 osteolytic, 4 osteoblastic and 2 mixed metastases. For most patients, the general morphology of the bone was well represented in the sCT images and osteolytic, osteoblastic and mixed lesions could be discriminated. Despite an average timespan between MR and CT acquisitions of 61 days, in bone, the average (± standard deviation) MAD was 116 ± 26 HU, MD - 14 ± 66 HU, DSC 0.85 ± 0.05, and RMSD 2.05 ± 0.48 mm and, in the lesion, MAD was 132 ± 62 HU, MD - 31 ± 106 HU, DSC 0.75 ± 0.2, and RMSD 2.73 ± 2.28 mm. CONCLUSIONS: Synthetic CT images adequately depicted the cancellous and cortical bone distribution in the different lesion types, which shows its potential for MRI-HIFU treatment planning. KEY POINTS: • Synthetic computed tomography was able to depict bone distribution in metastatic lesions. • Synthetic computed tomography images intrinsically aligned with treatment MR images may have the potential to facilitate MR-HIFU treatment planning of bone metastases, by combining visualization of soft tissues and cancellous and cortical bone.

Perfusion imaging of neuroblastoma and nephroblastoma in a paediatric population using pseudo-continuous arterial spin-labelling magnetic resonance imaging.

OBJECTIVES: To examine the feasibility of performing ASL-MRI in paediatric patients with solid abdominal tumours. METHODS: Multi-delay ASL data sets were acquired in ten paediatric patients diagnosed with either a neuroblastoma (n = 4) or nephroblastoma (n = 6) during a diagnostic MRI examination at a single visit (n = 4 at initial staging, n = 2 neuroblastoma and n = 2 nephroblastoma patients; n = 6 during follow-up, n = 2 neuroblastoma and n = 4 nephroblastoma patients). Visual evaluation and region-of-interest (ROI) analyses were performed on the processed perfusion-weighted images to assess ASL perfusion signal dynamics in the whole tumour, contralateral kidney, and tumour sub-regions with/without contrast enhancement. RESULTS: The majority of the included abdominal tumours presented with relatively low perfusion-weighted signal (PWS), especially compared with the highly perfused kidneys. Within the tumours, regions with high PWS were observed which, at short PLD, are possibly related to labelled blood inside vessels and at long PLD, reflect labelled blood accumulating inside tumour tissue over time. Conversely, comparison of ASL perfusion-weighted image findings with T1w enhancement after contrast administration showed that regions lacking contrast enhancement also were void of PWS. DISCUSSION: This pilot study demonstrates the feasibility of utilizing ASL-MRI in paediatric patients with solid abdominal tumours and provides a basis for further research on non-invasive perfusion measurements in this study population.

Feasibility of Velocity-Selective Arterial Spin Labeling in Breast Cancer Patients for Noncontrast-Enhanced Perfusion Imaging.

BACKGROUND: Dynamic contrast-enhanced (DCE) MRI is the most sensitive method for detection of breast cancer. However, due to high costs and retention of intravenously injected gadolinium-based contrast agent, screening with DCE-MRI is only recommended for patients who are at high risk for developing breast cancer. Thus, a noncontrast-enhanced alternative to DCE is desirable. PURPOSE: To investigate whether velocity selective arterial spin labeling (VS-ASL) can be used to identify increased perfusion and vascularity within breast lesions compared to surrounding tissue. STUDY TYPE: Prospective. POPULATION: Eight breast cancer patients. FIELD STRENGTH/SEQUENCE: A 3 T; VS-ASL with multislice single-shot gradient-echo echo-planar-imaging readout. ASSESSMENT: VS-ASL scans were independently assessed by three radiologists, with 3-25 years of experience in breast radiology. Scans were scored on lesion visibility and artifacts, based on a 3-point Likert scale. A score of 1 corresponded to "lesions being distinguishable from background" (lesion visibility), and "no or few artifacts visible, artifacts can be distinguished from blood signal" (artifact score). A distinction was made between mass and nonmass lesions (based on BI-RADS lexicon), as assessed in the standard clinical exam. STATISTICAL TESTS: Intra-class correlation coefficient (ICC) for interobserver agreement. RESULTS: The ICC was 0.77 for lesion visibility and 0.84 for the artifact score. Overall, mass lesions had a mean score of 1.27 on lesion visibility and 1.53 on the artifact score. Nonmass lesions had a mean score of 2.11 on lesion visibility and 2.11 on the artifact score. DATA CONCLUSION: We have demonstrated the technical feasibility of bilateral whole-breast perfusion imaging using VS-ASL in breast cancer patients. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Magnetic resonance imaging-based synthetic computed tomography of the lumbar spine for surgical planning: a clinical proof-of-concept.

OBJECTIVE: Computed tomography scanning of the lumbar spine incurs a radiation dose ranging from 3.5 mSv to 19.5 mSv as well as relevant costs and is commonly necessary for spinal neuronavigation. Mitigation of the need for treatment-planning CT scans in the presence of MRI facilitated by MRI-based synthetic CT (sCT) would revolutionize navigated lumbar spine surgery. The authors aim to demonstrate, as a proof of concept, the capability of deep learning-based generation of sCT scans from MRI of the lumbar spine in 3 cases and to evaluate the potential of sCT for surgical planning. METHODS: Synthetic CT reconstructions were made using a prototype version of the "BoneMRI" software. This deep learning-based image synthesis method relies on a convolutional neural network trained on paired MRI-CT data. A specific but generally available 4-minute 3D radiofrequency-spoiled T1-weighted multiple gradient echo MRI sequence was supplemented to a 1.5T lumbar spine MRI acquisition protocol. RESULTS: In the 3 presented cases, the prototype sCT method allowed voxel-wise radiodensity estimation from MRI, resulting in qualitatively adequate CT images of the lumbar spine based on visual inspection. Normal as well as pathological structures were reliably visualized. In the first case, in which a spiral CT scan was available as a control, a volume CT dose index (CTDIvol) of 12.9 mGy could thus have been avoided. Pedicle screw trajectories and screw thickness were estimable based on sCT findings. CONCLUSIONS: The evaluated prototype BoneMRI method enables generation of sCT scans from MRI images with only minor changes in the acquisition protocol, with a potential to reduce workflow complexity, radiation exposure, and costs. The quality of the generated CT scans was adequate based on visual inspection and could potentially be used for surgical planning, intraoperative neuronavigation, or for diagnostic purposes in an adjunctive manner.

Deep learning-enabled MRI-only photon and proton therapy treatment planning for paediatric abdominal tumours.

PURPOSE: To assess the feasibility of magnetic resonance imaging (MRI)-only treatment planning for photon and proton radiotherapy in children with abdominal tumours. MATERIALS AND METHODS: The study was conducted on 66 paediatric patients with Wilms' tumour or neuroblastoma (age 4 ± 2 years) who underwent MR and computed tomography (CT) acquisition on the same day as part of the clinical protocol. MRI intensities were converted to CT Hounsfield units (HU) by means of a UNet-like neural network trained to generate synthetic CT (sCT) from T1- and T2-weighted MR images. The CT-to-sCT image similarity was evaluated by computing the mean error (ME), mean absolute error (MAE), peak signal-to-noise ratio (PSNR) and Dice similarity coefficient (DSC). Synthetic CT dosimetric accuracy was verified against CT-based dose distributions for volumetric-modulated arc therapy (VMAT) and intensity-modulated pencil-beam scanning (PBS). Relative dose differences (Ddiff) in the internal target volume and organs-at-risk were computed and a three-dimensional gamma analysis (2 mm, 2%) was performed. RESULTS: The average ± standard deviation ME was -5 ± 12 HU, MAE was 57 ± 12 HU, PSNR was 30.3 ± 1.6 dB and DSC was 76 ± 8% for bones and 92 ± 9% for lungs. Average Ddiff were <0.5% for both VMAT (range [-2.5; 2.4]%) and PBS (range [-2.7; 3.7]%) dose distributions. The average gamma pass-rates were >99% (range [85; 100]%) for VMAT and >96% (range [87; 100]%) for PBS. CONCLUSION: The deep learning-based model generated accurate sCT from planning T1w- and T2w-MR images. Most dosimetric differences were within clinically acceptable criteria for photon and proton radiotherapy, demonstrating the feasibility of an MRI-only workflow for paediatric patients with abdominal tumours.

A computed tomography-based spatial reference for pedicle screw placement in adolescent idiopathic scoliosis.

STUDY DESIGN: Cross-sectional. OBJECTIVES: To determine semiautomatically the 3D position of the pedicle axis in operative adolescent idiopathic scoliosis (AIS) patients relative to the operating table and the lamina, as orientation for pedicle screw placement for better understanding and reference of spine surgeons. Pedicle morphology is well described as the angle between the convex and concave pedicle. However, the pedicle angle as relative to the neutral anterior-posterior axis or to an easy-to-use intravertebral landmark, remained unknown. METHODS: The pedicles of the apex and two adjacent vertebrae cranial and caudal to the apex of 86 right-sided primary thoracic AIS curves were evaluated using semiautomatic 3D software on high-resolution CT scans, in the same prone position as during surgery. Pedicle vectors were obtained and calculated as transverse and sagittal angles, as relative to the neutral axis (corresponding with an axis perpendicular to the operating table) and to an axis perpendicular to the lamina. RESULTS: At the apex, the mean convex and concave transverse pedicle angles were 14.3º (95% confidence interval [95% CI]: 12.0-16.6) and 30.4º (95% CI: 28.1-32.8) to the right. The angles decreased toward the adjacent levels cranial and caudal to the apex (p < 0.001) and linearly increased with a higher Cobb angle (r ≥ 0.472; p < 0.001). The mean transverse pedicle-lamina angles, sagittal pedicle angles and the sagittal pedicle-lamina angles differed along the curve as well (p < 0.001). CONCLUSIONS: Pedicle angulation differs between convex and concave and depends on the position of the vertebra relative to the apex, as well as the curve severity. The transverse and sagittal pedicle angles, as relative to the operating table and laminae, could provide useful reference for better understanding of the distorted 3D morphology, and the angles, as given in this study, could serve as an approximate guideline for the expected direction of the pedicle screw. LEVEL OF EVIDENCE: Level IV.

Comparison of multi-delay FAIR and pCASL labeling approaches for renal perfusion quantification at 3T MRI.

OBJECTIVE: To compare the most commonly used labeling approaches, flow-sensitive alternating inversion recovery (FAIR) and pseudocontinuous arterial spin labeling (pCASL), for renal perfusion measurement using arterial spin labeling (ASL) MRI. METHODS: Multi-delay FAIR and pCASL were performed in 16 middle-aged healthy volunteers on two different occasions at 3T. Relative perfusion-weighted signal (PWS), temporal SNR (tSNR), renal blood flow (RBF), and arterial transit time (ATT) were calculated for the cortex and medulla in both kidneys. Bland-Altman plots, intra-class correlation coefficient, and within-subject coefficient of variation were used to assess reliability and agreement between measurements. RESULTS: For the first visit, RBF was 362 ± 57 and 140 ± 47 mL/min/100 g, and ATT was 0.47 ± 0.13 and 0.70 ± 0.10 s in cortex and medulla, respectively, using FAIR; RBF was 201 ± 72 and 84 ± 27 mL/min/100 g, and ATT was 0.71 ± 0.25 and 0.86 ± 0.12 s in cortex and medulla, respectively, using pCASL. For both labeling approaches, RBF and ATT values were not significantly different between visits. Overall, FAIR showed higher PWS and tSNR. Moreover, repeatability of perfusion parameters was better using FAIR. DISCUSSION: This study showed that compared to (balanced) pCASL, FAIR perfusion values were significantly higher and more comparable between visits.

Dosimetric evaluation of synthetic CT for head and neck radiotherapy generated by a patch-based three-dimensional convolutional neural network.

PURPOSE: To develop and evaluate a patch-based convolutional neural network (CNN) to generate synthetic computed tomography (sCT) images for magnetic resonance (MR)-only workflow for radiotherapy of head and neck tumors. A patch-based deep learning method was chosen to improve robustness to abnormal anatomies caused by large tumors, surgical excisions, or dental artifacts. In this study, we evaluate whether the generated sCT images enable accurate MR-based dose calculations in the head and neck region. METHODS: We conducted a retrospective study on 34 patients with head and neck cancer who underwent both CT and MR imaging for radiotherapy treatment planning. To generate the sCTs, a large field-of-view T2-weighted Turbo Spin Echo MR sequence was used from the clinical protocol for multiple types of head and neck tumors. To align images as well as possible on a voxel-wise level, CT scans were nonrigidly registered to the MR (CTreg ). The CNN was based on a U-net architecture and consisted of 14 layers with 3 × 3 × 3 filters. Patches of 48 × 48 × 48 were randomly extracted and fed into the training. sCTs were created for all patients using threefold cross validation. For each patient, the clinical CT-based treatment plan was recalculated on sCT using Monaco TPS (Elekta). We evaluated mean absolute error (MAE) and mean error (ME) within the body contours and dice scores in air and bone mask. Also, dose differences and gamma pass rates between CT- and sCT-based plans inside the body contours were calculated. RESULTS: sCT generation took 4 min per patient. The MAE over the patient population of the sCT within the intersection of body contours was 75 ± 9 Hounsfield Units (HU) (±1 SD), and the ME was 9 ± 11 HU. Dice scores of the air and bone masks (CTreg vs sCT) were 0.79 ± 0.08 and 0.70 ± 0.07, respectively. Dosimetric analysis showed mean deviations of -0.03% ± 0.05% for dose within the body contours and -0.07% ± 0.22% inside the >90% dose volume. Dental artifacts obscuring the CT could be circumvented in the sCT by the CNN-based approach in combination with Turbo Spin Echo (TSE) magnetic resonance imaging (MRI) sequence that typically is less prone to susceptibility artifacts. CONCLUSIONS: The presented CNN generated sCTs from conventional MR images without adding scan time to the acquisition. Dosimetric evaluation suggests that dose calculations performed on the sCTs are accurate, and can therefore be used for MR-only radiotherapy treatment planning of the head and neck.

Surgical Outcomes of Anterior Versus Posterior Fusion in Lenke Type 1 Adolescent Idiopathic Scoliosis.

STUDY DESIGN: Retrospective study. OBJECTIVE: To describe surgical results in two and three dimensions and patient-reported outcomes of scoliosis treatment for Lenke type 1 idiopathic curves with an open anterior or posterior approach. SUMMARY OF BACKGROUND DATA: Different surgical techniques have been described to prevent curve progression and to restore spinal alignment in idiopathic scoliosis. The spine can be accessed via an anterior or a posterior approach. However, the surgical outcomes, especially in three dimensions, for different surgical approaches remain unclear. METHODS: Cohorts of Lenke curve type 1 idiopathic scoliosis patients, after anterior or posterior spinal fusion were recruited, to measure curve characteristics on conventional radiographs, before and after surgery and after 2 years follow-up, whereas the vertebral axial rotation, true mid-sagittal anterior-posterior height ratio of individual structures, and spinal height differences were measured on 3D reconstructions of the pre- and postoperative supine low-dose computed tomography (CT) scans. Additionally, the intraoperative parameters were described and the patients completed the Scoliosis Research Society outcomes and the 3-level version of EuroQol Group questionnaires postoperatively. RESULTS: Fifty-three patients with Lenke curve type 1 idiopathic scoliosis (26 in the anterior cohort and 27 in the posterior cohort) were analyzed. Fewer vertebrae were instrumented in the anterior cohort compared with the posterior cohort (P < 0.001), with less surgery time and lower intraoperative blood loss (P < 0.001). The Cobb angle correction of the primary thoracic curve directly after surgery was 57 ±â€Š12% in the anterior cohort and 73 ±â€Š12% in the posterior cohort (P < 0.001) and 55 ±â€Š13% and 66 ±â€Š12% (P = 0.001) at 2 years follow-up. Postoperative 3D alignment restoration and questionnaires showed no significant differences between the cohorts. CONCLUSION: This study suggests that Lenke type 1 curves can be effectively managed surgically with either an open anterior or posterior approach. Each approach, however, has specific advantages and challenges, as described in this study, which must be considered before treating each patient. LEVEL OF EVIDENCE: 3.

Anterior-posterior length discrepancy of the spinal column in adolescent idiopathic scoliosis-a 3D CT study.

BACKGROUND CONTEXT: One of the characteristics of reported observations in adolescent idiopathic scoliosis (AIS) is that the thoracic spine is longer anteriorly than posteriorly, more pronounced around the apex than the transitional zones. This reversal of the normal kyphotic anatomy of the thoracic spine is related to questions of etiopathogenesis of AIS. The changes in the anatomy of the anterior column have been described rather in detail; however, the role of the posterior spinal column and the laminae has so far not been elucidated. If the posterior column exhibits a longitudinal growth disturbance, it could act as a tether, leading to a more or less normal anterior column with a deformed and shorter posterior aspect of the spine. So far, it has remained unclear whether this anterior-posterior length discrepancy is the result of relative anterior lengthening or relative posterior shortening, and which tissues (bone, disc, intervertebral soft tissue) are involved. PURPOSE: The present study aimed to compare the discrepancy of the anterior-posterior length of the spinal column in the "true" midsagittal plane of each vertebra in patients with idiopathic scoliosis versus controls, using three-dimensional computed tomography (CT) scans. STUDY DESIGN/SETTING: This is a cross-sectional study. PATIENT SAMPLE: The sample consisted of computed tomography scans of 80 patients with moderate to severe AIS (Cobb angle: 46°-109°) before scoliosis navigation surgery and 30 non-scoliotic age-matched controls. OUTCOME MEASURES: The height of the osseous and non-osseous structures from anterior to posterior in the "true" midsagittal plane has been determined: the anterior side of the vertebral body and disc, the posterior side of the vertebral body and disc, the lamina and interlaminar space and the spinous process and interspinous space, as well as the height ratios between the anterior column and posterior structures of the primary thoracic and lumbar AIS curves and corresponding levels in non-scoliotic controls. METHODS: Semiautomatic software was used to reconstruct and measure the parameters in the true midsagittal plane of each vertebra and intervertebral structure that are rotated and tilted in a different way. RESULTS: In AIS, the anterior height of the thoracic curve was 3.6±2.8% longer than the posterior height, 2.0±6.1% longer than the length along the laminae, and 8.7±7.1% longer than the length along the spinous processes, and this differed significantly from controls (-2.7±2.4%, -7.4±5.2%, and +0.7±7.8%; p<.001). The absolute height of the osseous parts did not differ significantly between AIS and controls in the midsagittal plane. In contrast, the intervertebral structures contributed significantly to the observed length discrepancies. In absolute lengths, the anterior side of the disc of the thoracic curve was higher in AIS (5.4±0.8 mm) than controls (4.8±1.0 mm; p<.001), whereas the interspinous space was smaller in AIS (12.3±1.4 mm vs. 14.0±1.6 mm; p<.001). CONCLUSIONS: Based on this in vivo analysis, the true three-dimensional anterior-posterior length discrepancy of AIS curves was found to occur through both anterior column lengthening and posterior column shortening, with the facet joints functioning as the fulcrum. The vertebrae contribute partly to the anterior-posterior length discrepancy accompanied by more significant and possibly secondary increased anterior intervertebral discs height.

Benchmarking Distance Control and Virtual Drilling for Lateral Skull Base Surgery.

BACKGROUND: Novel audiovisual feedback methods were developed to improve image guidance during skull base surgery by providing audiovisual warnings when the drill tip enters a protective perimeter set at a distance around anatomic structures ("distance control") and visualizing bone drilling ("virtual drilling"). OBJECTIVE: To benchmark the drill damage risk reduction provided by distance control, to quantify the accuracy of virtual drilling, and to investigate whether the proposed feedback methods are clinically feasible. METHODS: In a simulated surgical scenario using human cadavers, 12 unexperienced users (medical students) drilled 12 mastoidectomies. Users were divided into a control group using standard image guidance and 3 groups using distance control with protective perimeters of 1, 2, or 3 mm. Damage to critical structures (sigmoid sinus, semicircular canals, facial nerve) was assessed. Neurosurgeons performed another 6 mastoidectomy/trans-labyrinthine and retro-labyrinthine approaches. Virtual errors as compared with real postoperative drill cavities were calculated. In a clinical setting, 3 patients received lateral skull base surgery with the proposed feedback methods. RESULTS: Users drilling with distance control protective perimeters of 3 mm did not damage structures, whereas the groups using smaller protective perimeters and the control group injured structures. Virtual drilling maximum cavity underestimations and overestimations were 2.8 ± 0.1 and 3.3 ± 0.4 mm, respectively. Feedback methods functioned properly in the clinical setting. CONCLUSION: Distance control reduced the risks of drill damage proportional to the protective perimeter distance. Errors in virtual drilling reflect spatial errors of the image guidance system. These feedback methods are clinically feasible.

Predicting clinical benefit from everolimus in patients with advanced solid tumors, the CPCT-03 study.

BACKGROUND: In this study, our aim was to identify molecular aberrations predictive for response to everolimus, an mTOR inhibitor, regardless of tumor type. METHODS: To generate hypotheses about potential markers for sensitivity to mTOR inhibition, drug sensitivity and genomic profiles of 835 cell lines were analyzed. Subsequently, a multicenter study was conducted. Patients with advanced solid tumors lacking standard of care treatment options were included and underwent a pre-treatment tumor biopsy to enable DNA sequencing of 1,977 genes, derive copy number profiles and determine activation status of pS6 and pERK. Treatment benefit was determined according to TTP ratio and RECIST. We tested for associations between treatment benefit and single molecular aberrations, clusters of aberrations and pathway perturbation. RESULTS: Cell line screens indicated several genes, such as PTEN (P = 0.016; Wald test), to be associated with sensitivity to mTOR inhibition. Subsequently 73 patients were included, of which 59 started treatment with everolimus. Response and molecular data were available from 43 patients. PTEN aberrations, i.e. copy number loss or mutation, were associated with treatment benefit (P = 0.046; Fisher's exact test). CONCLUSION: Loss-of-function aberrations in PTEN potentially represent a tumor type agnostic biomarker for benefit from everolimus and warrants further confirmation in subsequent studies.

Upright, prone, and supine spinal morphology and alignment in adolescent idiopathic scoliosis.

BACKGROUND: Patients with adolescent idiopathic scoliosis (AIS) are usually investigated by serial imaging studies during the course of treatment, some imaging involves ionizing radiation, and the radiation doses are cumulative. Few studies have addressed the correlation of spinal deformity captured by these different imaging modalities, for which patient positioning are different. To the best of our knowledge, this is the first study to compare the coronal, axial, and sagittal morphology of the scoliotic spine in three different body positions (upright, prone, and supine) and between three different imaging modalities (X-ray, CT, and MRI). METHODS: Sixty-two AIS patients scheduled for scoliosis surgery, and having undergone standard pre-operative work-up, were included. This work-up included upright full-spine radiographs, supine bending radiographs, supine MRI, and prone CT as is the routine in one of our institutions. In all three positions, Cobb angles, thoracic kyphosis (TK), lumbar lordosis (LL), and vertebral rotation were determined. The relationship among three positions (upright X-ray, prone CT, and supine MRI) was investigated according to the Bland-Altman test, whereas the correlation was described by the intraclass correlation coefficient (ICC). RESULTS: Thoracic and lumbar Cobb angles correlated significantly between conventional radiographs (68° ± 15° and 44° ± 17°), prone CT (54° ± 15° and 33° ± 15°), and supine MRI (57° ± 14° and 35° ± 16°; ICC ≥0.96; P < 0.001). The thoracic and lumbar apical vertebral rotation showed a good correlation among three positions (upright, 22° ± 12° and 11° ± 13°; prone, 20° ± 9° and 8° ± 11°; supine, 16° ± 11° and 6° ± 14°; ICC ≥0.82; P < 0.001). The TK and LL correlated well among three different positions (TK 26° ± 11°, 22° ± 12°, and 17° ± 10°; P ≤ 0.004; LL 49° ± 12°, 45° ± 11°, and 44° ± 12°; P < 0.006; ICC 0.87 and 0.85). CONCLUSIONS: Although there is a generalized underestimation of morphological parameters of the scoliotic deformity in the supine and prone positions as compared to the upright position, a significant correlation of these parameters is still evident among different body positions by different imaging modalities. Findings of this study suggest that severity of scoliotic deformity in AIS patients can be largely represented by different imaging modalities despite the difference in body positioning.

Detailed imaging and genetic analysis reveal a secondary BRAF(L505H) resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib.

Resistance to treatment is the main problem of targeted treatment for cancer. We followed ten patients during treatment with vemurafenib, by three-dimensional imaging. In all patients, only a subset of lesions progressed. Next-generation DNA sequencing was performed on sequential biopsies in four patients to uncover mechanisms of resistance. In two patients, we identified mutations that explained resistance to vemurafenib; one of these patients had a secondary BRAF L505H mutation. This is the first observation of a secondary BRAF mutation in a vemurafenib-resistant patient-derived melanoma sample, which confirms the potential importance of the BRAF L505H mutation in the development of therapy resistance. Moreover, this study hints toward an important role for tumor heterogeneity in determining the outcome of targeted treatments.

Evolution of the ablation region after magnetic resonance-guided high-intensity focused ultrasound ablation in a Vx2 tumor model.

OBJECTIVES: Volumetric magnetic resonance (MR)-guided high-intensity focused ultrasound (HIFU) is a completely noninvasive image-guided thermal ablation technique. Recently, there has been growing interest in the use of MR-HIFU for noninvasive ablation of malignant tumors. Of particular interest for noninvasive ablation of malignant tumors is reliable treatment monitoring and evaluation of response. At this point, there is limited evidence on the evolution of the ablation region after MR-HIFU treatment. The purpose of the present study was to comprehensively characterize the evolution of the ablation region after volumetric MR-HIFU ablation in a Vx2 tumor model using MR imaging, MR temperature data, and histological data. MATERIALS AND METHODS: Vx2 tumors in the hind limb muscle of New Zealand White rabbits (n = 30) were ablated using a clinical MR-HIFU system. Twenty-four animals were available for analyses. Magnetic resonance imaging was performed before and immediately after ablation; MR temperature mapping was performed during the ablation. The animals were distributed over 7 groups with different follow-up lengths. Depending on the group, animals were reimaged and then killed on day 0, 1, 3, 7, 14, 21, or 28 after ablation. For all time points, the size of nonperfused areas (NPAs) on contrast-enhanced T1-weighted (CE-T1-w) images was compared with lethal thermal dose areas (ie, the tissue area that received a thermal dose of 240 equivalent minutes or greater [EM] at 43°C) and with the necrotic tissue areas on histology sections. RESULTS: The NPA on CE-T1-w imaging showed an increase in median size from 266 ± 148 to 392 ± 178 mm(2) during the first day and to 343 ± 170 mm(2) on day 3, followed by a gradual decrease to 113 ± 103 mm(2) on day 28. Immediately after ablation, the NPA was 1.6 ± 1.4 times larger than the area that received a thermal dose of 240 EM or greater in all animals. The median size of the necrotic area on histology was 1.7 ± 0.4 times larger than the NPA immediately after ablation. After 7 days, the size of the NPA was in agreement with the necrotic tissue area on histology (ratio, 1.0 ± 0.2). CONCLUSIONS: During the first 3 days after MR-HIFU ablation, the ablation region increases in size, after which it gradually decreases in size. The NPA on CE-T1-w imaging underestimates the extent of tissue necrosis on histology in the initial few days, but after 1 week, the NPA is reliable in delineating the necrotic tissue area. The 240-EM thermal dose limit underestimates the necrotic tissue area immediately after MR-HIFU ablation. Reliable treatment evaluation techniques are particularly important for noninvasive, image-guided tumor ablation. Our results indicate that CE-T1-w imaging is reliable for MR-HIFU treatment evaluation after 1 week.

A transoesophageal echocardiographic image acquisition protocol for wide-view fusion of three-dimensional datasets to support atrial fibrillation catheter ablation.

PURPOSE: The aim of this paper is to propose a transoesophageal echocardiography (TOE) image acquisition protocol which provides a systematic manner of acquiring a minimal number of overlapping 3D TOE datasets allowing the reconstruction of a wide 3D view of the left atrium (LA) with anatomical landmarks that are important for atrial fibrillation catheter ablation. METHODS: In eight cardiac surgical patients, 3D TOE datasets were acquired with a six-step protocol. In the protocol, step 1 aims to acquire the central view of the mitral valve (MV), aortic valve (AV) and left atrial appendage (LAA). Step 2 was developed to acquire the left pulmonary veins (PVs) and step 3 to acquire the right PVs. Steps 4, 5 and 6 were developed to create a sufficient overlap between different datasets. 3D TOE datasets were registered and fused manually in end diastole. RESULTS: The image acquisition protocol was feasible in all patients. In the fused 3D dataset, a wide 3D view of the LA is shown, and left and right PVs could be seen simultaneously. The LAA, MV, AV and fossa ovalis (FO) were visualised clearly in the 3D TOE datasets. The PV ostia, which are located at the edges of the 3D datasets, suffered more from the artefact of echo loss. The volume overlaps between neighbouring TOE datasets were 50-75 %. CONCLUSION: The major part of the LA anatomy incorporating the PVs, LAA, MV, AV and FO as important anatomical landmarks can be reconstructed by registering and fusing 3D datasets acquired with the six-step TOE image acquisition protocol.

Validation of exposure visualization and audible distance emission for navigated temporal bone drilling in phantoms.

BACKGROUND: A neuronavigation interface with extended function as compared with current systems was developed to aid during temporal bone surgery. The interface, named EVADE, updates the prior anatomical image and visualizes the bone drilling process virtually in real-time without need for intra-operative imaging. Furthermore, EVADE continuously calculates the distance from the drill tip to segmented temporal bone critical structures (e.g. the sigmoid sinus and facial nerve) and produces audiovisual warnings if the surgeon drills in too close vicinity. The aim of this study was to evaluate the accuracy and surgical utility of EVADE in physical phantoms. METHODOLOGY/PRINCIPAL FINDINGS: We performed 228 measurements assessing the position accuracy of tracking a navigated drill in the operating theatre. A mean target registration error of 1.33±0.61 mm with a maximum error of 3.04 mm was found. Five neurosurgeons each drilled two temporal bone phantoms, once using EVADE, and once using a standard neuronavigation interface. While using standard neuronavigation the surgeons damaged three modeled temporal bone critical structures. No structure was hit by surgeons utilizing EVADE. Surgeons felt better orientated and thought they had improved tumor exposure with EVADE. Furthermore, we compared the distances between surface meshes of the virtual drill cavities created by EVADE to actual drill cavities: average maximum errors of 2.54±0.49 mm and -2.70±0.48 mm were found. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that EVADE gives accurate feedback which reduces risks of harming modeled critical structures compared to a standard neuronavigation interface during temporal bone phantom drilling.