Rakhee Gawande

Ionising radiation-free whole-body MRI versus 18F-fluorodeoxyglucose PET/CT scans for children and young adults with cancer: A prospective, non-randomised, single-centre study

BACKGROUND Imaging tests are essential for staging of children with cancer. However, CT and radiotracer-based imaging procedures are associated with substantial exposure to ionising radiation and risk of secondary cancer development later in life. Our aim was to create a highly effective, clinically feasible, ionising radiation-free staging method based on whole-body diffusion-weighted MRI and the iron supplement ferumoxytol, used off-label as a contrast agent. METHODS We compared whole-body diffusion-weighted MRI with standard clinical (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT scans in children and young adults with malignant lymphomas and sarcomas. Whole-body diffusion-weighted magnetic resonance images were generated by coregistration of colour-encoded ferumoxytol-enhanced whole-body diffusion-weighted MRI scans for tumour detection with ferumoxytol-enhanced T1-weighted MRI scans for anatomical orientation, similar to the concept of integrated (18)F-FDG PET/CT scans. Tumour staging results were compared using Cohens κ statistics. Histopathology and follow-up imaging served as the standard of reference. Data was assessed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01542879. FINDINGS 22 of 23 recruited patients were analysed because one patient discontinued before completion of the whole-body scan. Mean exposure to ionising radiation was 12·5 mSv (SD 4·1) for (18)F-FDG PET/CT compared with zero for whole-body diffusion-weighted MRI. (18)F-FDG PET/CT detected 163 of 174 malignant lesions at 1325 anatomical regions and whole-body diffusion-weighted MRI detected 158. Comparing (18)F-FDG PET/CT to whole-body diffusion-weighted MRI, sensitivities were 93·7% (95% CI 89·0-96·8) versus 90·8% (85·5-94·7); specificities 97·7% (95% CI 96·7-98·5) versus 99·5% (98·9-99·8); and diagnostic accuracies 97·2% (93·6-99·4) versus 98·3% (97·4-99·2). Tumour staging results showed very good agreement between both imaging modalities with a κ of 0·93 (0·81-1·00). No adverse events after administration of ferumoxytol were recorded. INTERPRETATION Ferumoxytol-enhanced whole-body diffusion-weighted MRI could be an alternative to (18)F-FDG PET/CT for staging of children and young adults with cancer that is free of ionising radiation. This new imaging test might help to prevent long-term side-effects from radiographic staging procedures. FUNDING Thrasher Research Fund and Clinical Health Research Institute at Stanford University.

Ferumoxytol: a new, clinically applicable label for stem-cell tracking in arthritic joints with MRI

AIM To develop a clinically applicable MRI technique for tracking stem cells in matrix-associated stem-cell implants, using the US FDA-approved iron supplement ferumoxytol. MATERIALS & METHODS Ferumoxytol-labeling of adipose-derived stem cells (ADSCs) was optimized in vitro. A total of 11 rats with osteochondral defects of both femurs were implanted with ferumoxytol- or ferumoxides-labeled or unlabeled ADSCs, and underwent MRI up to 4 weeks post matrix-associated stem-cell implant. The signal-to-noise ratio of different matrix-associated stem-cell implant was compared with t-tests and correlated with histopathology. RESULTS An incubation concentration of 500 µg iron/ml ferumoxytol and 10 µg/ml protamine sulfate led to significant cellular iron uptake, T2 signal effects and unimpaired ADSC viability. In vivo, ferumoxytol- and ferumoxides-labeled ADSCs demonstrated significantly lower signal-to-noise ratio values compared with unlabeled controls (p < 0.01). Histopathology confirmed engraftment of labeled ADSCs, with slow dilution of the iron label over time. CONCLUSION Ferumoxytol can be used for in vivo tracking of stem cells with MRI.

Intravenous ferumoxytol allows noninvasive MR imaging monitoring of macrophage migration into stem cell transplants

PURPOSE To develop a clinically applicable imaging technique for monitoring differential migration of macrophages into viable and apoptotic matrix-associated stem cell implants (MASIs) in arthritic knee joints. MATERIALS AND METHODS With institutional animal care and use committee approval, six athymic rats were injected with intravenous ferumoxytol (0.5 mmol iron per kilogram of body weight) to preload macrophages of the reticuloendothelial system with iron oxide nanoparticles. Forty-eight hours later, all animals received MASIs of viable adipose-derived stem cells (ADSCs) in an osteochondral defect of the right femur and mitomycin-pretreated apoptotic ADSCs in an osteochondral defect of the left femur. One additional control animal each received intravenous ferumoxytol and bilateral scaffold-only implants (without cells) or bilateral MASIs without prior ferumoxytol injection. All knees were imaged with a 7.0-T magnetic resonance (MR) imaging unit with T2-weighted fast spin-echo sequences immediately after, as well as 2 and 4 weeks after, matrix-associated stem cell implantation. Signal-to-noise ratios (SNRs) of viable and apoptotic MASIs were compared by using a linear mixed-effects model. MR imaging data were correlated with histopathologic findings. RESULTS All ADSC implants showed a slowly decreasing T2 signal over 4 weeks after matrix-associated stem cell implantation. SNRs decreased significantly over time for the apoptotic implants (SNRs on the day of matrix-associated stem cell implantation, 2 weeks after the procedure, and 4 weeks after the procedure were 16.9, 10.9, and 6.7, respectively; P = .0004) but not for the viable implants (SNRs on the day of matrix-associated stem cell implantation, 2 weeks after the procedure, and 4 weeks after the procedure were 17.7, 16.2, and 15.7, respectively; P = .2218). At 4 weeks after matrix-associated stem cell implantation, SNRs of apoptotic ADSCs were significantly lower than those of viable ADSCs (mean, 6.7 vs 15.7; P = .0013). This corresponded to differential migration of iron-loaded macrophages into MASIs. CONCLUSION Iron oxide loading of macrophages in the reticuloendothelial system by means of intravenous ferumoxytol injection can be utilized to monitor differential migration of bone marrow macrophages into viable and apoptotic MASIs in a rat model.

Magnetic Resonance Imaging of Ferumoxide-Labeled Mesenchymal Stem Cells in Cartilage Defects: In Vitro and in Vivo Investigations

The purpose of this study was to (1) compare three different techniques for ferumoxide labeling of mesenchymal stem cells (MSCs), (2) evaluate if ferumoxide labeling allows in vivo tracking of matrix-associated stem cell implants (MASIs) in an animal model, and (3) compare the magnetic resonance imaging (MRI) characteristics of ferumoxide-labeled viable and apoptotic MSCs. MSCs labeled with ferumoxide by simple incubation, protamine transfection, or Lipofectin transfection were evaluated with MRI and histopathology. Ferumoxide-labeled and unlabeled viable and apoptotic MSCs in osteochondral defects of rat knee joints were evaluated over 12 weeks with MRI. Signal to noise ratios (SNRs) of viable and apoptotic labeled MASIs were tested for significant differences using t-tests. A simple incubation labeling protocol demonstrated the best compromise between significant magnetic resonance signal effects and preserved cell viability and potential for immediate clinical translation. Labeled viable and apoptotic MASIs did not show significant differences in SNR. Labeled viable but not apoptotic MSCs demonstrated an increasing area of T2 signal loss over time, which correlated to stem cell proliferation at the transplantation site. Histopathology confirmed successful engraftment of viable MSCs. The engraftment of iron oxide–labeled MASIs by simple incubation can be monitored over several weeks with MRI. Viable and apoptotic MASIs can be distinguished via imaging signs of cell proliferation at the transplantation site.

Chest CT in children: anesthesia and atelectasis.

BackgroundThere has been an increasing tendency for anesthesiologists to be responsible for providing sedation or anesthesia during chest CT imaging in young children. Anesthesia-related atelectasis noted on chest CT imaging has proven to be a common and troublesome problem, affecting image quality and diagnostic sensitivity.ObjectiveTo evaluate the safety and effectiveness of a standardized anesthesia, lung recruitment, controlled-ventilation technique developed at our institution to prevent atelectasis for chest CT imaging in young children.Materials and methodsFifty-six chest CT scans were obtained in 42 children using a research-based intubation, lung recruitment and controlled-ventilation CT scanning protocol. These studies were compared with 70 non-protocolized chest CT scans under anesthesia taken from 18 of the same children, who were tested at different times, without the specific lung recruitment and controlled-ventilation technique. Two radiology readers scored all inspiratory chest CT scans for overall CT quality and atelectasis. Detailed cardiorespiratory parameters were evaluated at baseline, and during recruitment and inspiratory imaging on 21 controlled-ventilation cases and 8 control cases.ResultsSignificant differences were noted between groups for both quality and atelectasis scores with optimal scoring demonstrated in the controlled-ventilation cases where 70% were rated very good to excellent quality scans compared with only 24% of non-protocol cases. There was no or minimal atelectasis in 48% of the controlled ventilation cases compared to 51% of non-protocol cases with segmental, multisegmental or lobar atelectasis present. No significant difference in cardiorespiratory parameters was found between controlled ventilation and other chest CT cases and no procedure-related adverse events occurred.ConclusionControlled-ventilation infant CT scanning under general anesthesia, utilizing intubation and recruitment maneuvers followed by chest CT scans, appears to be a safe and effective method to obtain reliable and reproducible high-quality, motion-free chest CT images in children.

Progressing Toward a Cohesive Pediatric 18F-FDG PET/MR Protocol: Is Administration of Gadolinium Chelates Necessary?

With the increasing availability of integrated PET/MR scanners, the utility and need for MR contrast agents for combined scans is questioned. The purpose of our study was to evaluate whether administration of gadolinium chelates is necessary for evaluation of pediatric tumors on 18F-FDG PET/MR images. Methods: First, in 119 pediatric patients with primary and secondary tumors, we used 14 diagnostic criteria to compare the accuracy of several MR sequences: unenhanced T2-weighted fast spin-echo imaging; unenhanced diffusion-weighted imaging; and—before and after gadolinium chelate contrast enhancement—T1-weighted 3-dimensional spoiled gradient echo LAVA (liver acquisition with volume acquisition) imaging. Next, in a subset of 36 patients who had undergone 18F-FDG PET within 3 wk of MRI, we fused the PET images with the unenhanced T2-weighted MR images (unenhanced 18F-FDG PET/MRI) and the enhanced T1-weighted MR images (enhanced 18F-FDG PET/MRI). Using the McNemar test, we compared the accuracy of the two types of fused images using the 14 diagnostic criteria. We also evaluated the concordance between 18F-FDG avidity and gadolinium chelate enhancement. The standard of reference was histopathologic results, surgical notes, and follow-up imaging. Results: There was no significant difference in diagnostic accuracy between the unenhanced and enhanced MR images. Accordingly, there was no significant difference in diagnostic accuracy between the unenhanced and enhanced 18F-FDG PET/MR images. 18F-FDG avidity and gadolinium chelate enhancement were concordant in 30 of the 36 patients and 106 of their 123 tumors. Conclusion: Gadolinium chelate administration is not necessary for accurate diagnostic characterization of most solid pediatric malignancies on 18F-FDG PET/MR images, with the possible exception of focal liver lesions.

Opsoclonus–myoclonus due to underlying ganglioneuroblastoma

Imaging description A 19-month-old child presented with symptoms of difficulty in walking, abnormal eye and limb movements, and irritability. MRI of the brain for suspected cerebellar ataxia was unremarkable (Fig. 16.1a, b). CT scan of the neck and chest revealed a small left paraspinal soft tissue lesion at the level of T1 and T2 (Fig. 16.1c–e) and a diagnosis of neuroblastoma-associated opsoclonus–myoclonus syndrome (OMS) was suggested. Metaiodobenzylguanidine scintigraphy (MIBG) scan was negative (Fig. 16.1f). Excision biopsy of the mass confirmed the diagnosis of a ganglioneuroblastoma. Importance OMS, also known as dancing eye syndrome, is a rare disorder that presents in early childhood with involuntary rapid eye movements, myoclonic limb jerking, ataxia, and behavioral changes. It can be idiopathic, postinfectious, or a paraneoplastic manifestation of neuroblastoma. OMS is associated with neuroblastoma in 40% of patients and occurs between the ages of six months and three years in these patients. Conversely, only about 2% of patients with neuroblastoma present with OMS. In children, OMS may occur as a paraneoplastic manifestation of all neural crest tumors, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. The pathogenesis of OMS is thought to be immune-mediated, with a cross-reactive autoimmunity between neuroblastoma cells and the central nervous system. Neuroblastomas associated with OMS tend to be low grade, thoracic in location, and have a more favorable outcome than non-OMS neuroblastomas. Neuroblastomas associated with OMS are usually very small in size and present a diagnostic challenge as they are less metabolically active and urinary catecholamines or MIBG scans can be negative. CT and/or MRI of the neck, chest, abdomen, and pelvis are the most sensitive studies to detect these occult neuroblastomas (Fig. 16.1).