Srinivasan Mukundan

A liposomal nanoscale contrast agent for preclinical CT in mice

OBJECTIVE The goal of this study was to determine if an iodinated, liposomal contrast agent could be used for high-resolution, micro-CT of low-contrast, small-size vessels in a murine model. MATERIALS AND METHODS A second-generation, liposomal blood pool contrast agent encapsulating a high concentration of iodine (83-105 mg I/mL) was evaluated. A total of five mice weighing between 20 and 28 g were infused with equivalent volume doses (500 microL of contrast agent/25 g of mouse weight) and imaged with our micro-CT system for intervals of up to 240 min postinfusion. The animals were anesthetized, mechanically ventilated, and vital signs monitored allowing for simultaneous cardiac and respiratory gating of image acquisition. RESULTS Initial enhancement of about 900 H in the aorta was obtained, which decreased to a plateau level of approximately 800 H after 2 hr. Excellent contrast discrimination was shown between the myocardium and cardiac blood pool (650-700 H). No significant nephrogram was identified, indicating the absence of renal clearance of the agent. CONCLUSION The liposomal-based iodinated contrast agent shows long residence time in the blood pool, very high attenuation within submillimeter vessels, and no significant renal clearance rendering it an effective contrast agent for murine vascular imaging using a micro-CT scanner.

A retrospective analysis of facial fracture etiologies

The medical records of 437 patients with 929 facial fractures were retrospectively analyzed. Fracture patterns were classified based on the presence or absence of fractures in each of 4 anatomic subunits (frontal, upper midface, lower midface, and mandible). The most common etiology of trauma was assault (36%), followed by motor vehicle collision (MVC, 32%), fall (18%), sports (11%), occupational (3%), and gunshot wound (GSW, 2%). The most common fracture type was nasal bone fracture (164). MVC was found to be a significant predictor of panfacial fractures, as was GSW. Sports injuries were a significant predictor of isolated upper midface fractures, and assault was a significant predictor for isolated mandible fractures. MVC and GSW each were found to lead to significantly higher severity of injury than assault, fall, and sports. The results confirm intuitive aspects of the etiology of facial fractures that have been anecdotally supported in the past.

Improved measurement of pressure gradients in aortic coarctation by magnetic resonance imaging.

OBJECTIVES This study evaluated whether magnetic resonance imaging (MRI) and magnetic resonance (MR) phase velocity mapping could provide accurate estimates of stenosis severity and pressure gradients in aortic coarctation. BACKGROUND Clinical management of aortic coarctation requires determination of lesion location and severity and quantification of the pressure gradient across the constricted area. METHODS Using a series of anatomically accurate models of aortic coarctation, the laboratory portion of this study found that the loss coefficient (K), commonly taken to be 4.0 in the simplified Bernoulli equation delta P = KV2, was a function of stenosis severity. The values of the loss coefficient ranged from 2.8 for a 50% stenosis to 4.9 for a 90% stenosis. Magnetic resonance imaging and MR phase velocity mapping were then used to determine coarctation severity and pressure gradient in 32 patients. RESULTS Application of the new severity-dependent loss coefficients found that pressure gradients deviated from 1 to 17 mm Hg compared with calculations made with the commonly used value of 4.0. Comparison of MR estimates of pressure gradient with Doppler ultrasound estimates (in 22 of 32 patients) and with catheter pressure measurements (in 6 of 32 patients) supports the conclusion that the severity-based loss coefficient provides improved estimates of pressure gradients. CONCLUSIONS This study suggests that MRI could be used as a complete diagnostic tool for accurate evaluation of aortic coarctation, by determining stenosis location and severity and by accurately estimating pressure gradients.

The neurosurgical anatomy of the sphenoid sinus and sellar floor in endoscopic transsphenoidal surgery

OBJECT A considerable degree of variability exists in the anatomy of the sphenoid sinus, sella turcica, and surrounding skull base structures. The authors aimed to characterize neuroimaging and intraoperative variations in the sagittal and coronal surgical anatomy of healthy controls and patients with sellar lesions. METHODS Magnetic resonance imaging studies obtained in 100 healthy adults and 78 patients with sellar lesions were reviewed. The following measurements were made on midline sagittal images: sellar face, sellar prominence, sellar angle, tuberculum sellae angle, sellar-clival angle, length of planum sphenoidale, and length of clivus. The septal configuration of the sphenoid sinus was classified as either simple or complex, according to the number of septa, their symmetry, and their morphological features. The following measurements were made on coronal images: maximum width of the sphenoid sinus and sellar face, and the distance between the parasellar and midclivus internal carotid arteries. Neuroimaging results were correlated with intraoperative findings during endoscopic transsphenoidal surgery. RESULTS Three sellar floor morphologies were defined in normal adults: prominent (sellar angle of < 90°) in 25%, curved (sellar angle 90-150°) in 63%, flat (sellar angle > 150°) in 11%, and no floor (conchal sphenoid) in 1%. In healthy adults, the following mean measurements were obtained: sellar face, 13.4 mm; sellar prominence, 3.0 mm; sellar angle, 112°; angle of tuberculum sellae, 112°; and sellar-clival angle, 117°. Compared with healthy adults, patients with sellar lesions were more likely to have prominent sellar types (43% vs 25%, p = 0.01), a more acute sellar angle (102° vs 112°, p = 0.03), a more prominent sellar floor (3.8 vs 3.0 mm, p < 0.005), and more acute tuberculum (105° vs 112°, p < 0.01) and sellar-clival (105° vs 117°, p < 0.003) angles. A flat sellar floor was more difficult to identify intraoperatively and more likely to require the use of a chisel or drill to expose (75% vs 25%, p = 0.01). A simple sphenoid sinus configuration (no septa, 1 vertical septum, or 2 symmetric vertical septa) was noted in 71% of studies, and the other 29% showed a complex configuration (2 or more asymmetrical septa, 3 or more septa of any kind, or the presence of a horizontal septum). Intraoperative correlation was more challenging in cases with complex sinus anatomy; the most reliable intraoperative midline markers were the vomer, superior sphenoid rostrum, and bilateral parasellar and clival carotid protuberances. CONCLUSIONS Preoperative assessment of neuroimaging studies is critical for characterizing the morphological characteristics of the sphenoid sinus, sellar floor, tuberculum sellae, and clivus. The flat sellar type identified in 11% of people) or a complex sphenoid sinus configuration (in 29% of people) may make intraoperative correlation substantially more challenging. An understanding of the regional anatomy and its variability can improve the safety and accuracy of transsphenoidal and extended endoscopic skull base approaches.

MOSFET Dosimetry for Radiation Dose Assessment of Bismuth Shielding of the Eye in Children

OBJECTIVE The purpose of our study was to measure radiation dose to the orbit during pediatric cranial CT with and without bismuth shielding using a novel dosimetry system. Cranial CT was performed on a pediatric anthropomorphic phantom, with and without bismuth eye shields. A solid-state metal oxide semiconductor field effect transistor (MOSFET) dosimeter was used to obtain real-time dose measurements. CONCLUSION Bismuth shielding reduced radiation dose to the eye by up to 42%; shield artifact fell outside the diagnostic area of interest.

PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma

Primary central nervous system (CNS) lymphoma (PCNSL) and primary testicular lymphoma (PTL) are rare extranodal large B-cell lymphomas with similar genetic signatures. There are no standard-of-care treatment options for patients with relapsed and refractory PCNSL and PTL, and the overall prognosis is poor. PCNSLs and PTLs exhibit frequent 9p24.1 copy-number alterations and infrequent translocations of 9p24.1 and associated increased expression of the programmed cell death protein 1 (PD-1) ligands, PD-L1 and PD-L2. The activity of PD-1 blockade in other lymphomas with 9p24.1 alterations prompted us to test the efficacy of the anti-PD1 antibody, nivolumab, in 4 patients with relapsed/refractory PCNSL and 1 patient with CNS relapse of PTL. All 5 patients had clinical and radiographic responses to PD-1 blockade, and 3 patients remain progression-free at 13+ to 17+ months. Our data suggest that nivolumab is active in relapsed/refractory PCNSL and PTL and support further investigation of PD-1 blockade in these diseases.

Management of newly diagnosed glioblastoma: guidelines development, value and application

The movement to create guidelines for management of medical maladies has been gaining strength for quality, academic, financial and political purposes over the past two decades. This applies to neurological diseases, too. Evidence-based guidelines created in a multidisciplinary fashion using predetermined criteria for grading scientific data and translating this to similarly ranked recommendations is a valuable approach to meeting this goal. The following is a summary of the methods used for, and the results of, an evidence-based guideline for the management of newly diagnosed glioblastoma. In addition to outlining recommendations by discipline, it also addresses how concerns and conflicts were addressed in their development and provides comment on future directions in management of this situation that may improve outcome. It is important that clinicians directly experienced in patient management take the lead in creation of guidelines related to the diseases they deal with, as these clinicians are clearly the most suited to being able to arrive at a meaningful and useful product.

Four-dimensional MR microscopy of the mouse heart using radial acquisition and liposomal gadolinium contrast agent

Magnetic resonance microscopy (MRM) has become an important tool for small animal cardiac imaging. In relation to competing technologies (microCT and ultrasound), MR is limited by spatial resolution, temporal resolution, and acquisition time. All three of these limitations have been addressed by developing a four‐dimensional (4D) (3D plus time) radial acquisition (RA) sequence. The signal‐to‐noise ratio (SNR) has been optimized by minimizing the echo time (TE) (300 us). The temporal resolution and throughput have been improved by center‐out trajectories resulting in repetition time (TR) <2.5 ms. The contrast has been enhanced through the use of a liposomal blood pool agent that reduces the T1 of the blood to <400 ms. We have developed protocols for three specific applications: 1) high‐throughput with spatial resolution of 87 × 87 × 352 um3 (voxel volume = 2.7 nL) and acquisition time of 16 min; 2) high‐temporal resolution with spatial resolution of 87 × 87 × 352 um3 (voxel volume = 2.7 nL) and temporal resolution at 4.8 ms and acquisition time of 32 minutes; and 3) high‐resolution isotropic imaging at 87 × 87 × 87 um3 (voxel volume = 0.68 nL) and acquisition time of 31 min. The 4D image arrays allow direct measure of cardiac functional parameters dependent on chamber volumes, e.g., ejection fraction (EF), end diastolic volume (EDV), and end systolic volume (ESV). Magn Reson Med 60:111–118, 2008.

External volume expansion increases subcutaneous thickness, cell proliferation, and vascular remodeling in a murine model.

Background: Fat grafting is a powerful tool for soft-tissue reconstruction; however, the science behind recipient bed preparation has not been thoroughly explored. External volume expansion using suction before fat grafting has been used clinically to improve reliability and consistency of graft survival. The authors developed a murine model to investigate the underlying mechanism of external volume expansion. Methods: The authors created an external volume expansion device using a soft-silicone dome connected to a vacuum source (25 mmHg) to treat the dorsum of mice, and the response was compared with treatment with an occlusive dressing. Treated areas were monitored with magnetic resonance imaging. Remodeling of microvasculature was studied with corrosion casting on day 7. Effects on tissue thickness, number of adipocytes, cell proliferation, and blood vessel density were analyzed at 28 days. Results: Macroscopic analysis showed tissue swelling at sites treated with the external volume expansion device by 21 days, without skin damage. On day 28, external volume expansion increased the thickness of the subcutaneous fat layer twofold, consistent with magnetic resonance imaging observations. The proliferation rate in the subcutaneous layer of expansion-treated areas increased twofold, with a net 2.2-fold increase in number of adipocytes in columns; remodeling of the vessels network occurred, with reorientation and increase of vessel diameters shown by corrosion casting and 1.9-fold augmentation of vessels density. Conclusions: External volume expansion applied to mouse integument induces highly proliferative and vascularized subcutaneous tissue. Recipient-site preparation using external volume expansion devices may be a promising tool to enhance cell and tissue engraftment.

Variation in Use of Head Computed Tomography by Emergency Physicians

OBJECTIVE Variation in emergency department head computed tomography (CT) use in patients with atraumatic headaches between hospitals is being measured nationwide. However, the magnitude of interphysician variation within a hospital is currently unknown. We hypothesized that there was significant variation in the rates of physician head CT use, both overall and for patients diagnosed with atraumatic headaches. METHODS This cross-sectional study was conducted in the emergency department of a large urban academic hospital, and institutional review board approval was obtained. All emergency department visits from 2009 were analyzed, and the primary outcome measure was whether or not head CT was performed. Logistic regression was used to control for patient, physician, and visit characteristics potentially associated with head CT ordering. The degree of interphysician variability was tested, both before and after controlling for these variables. RESULTS Of 55,286 emergency department patient encounters, 4919 (8.9%) involved head CT examinations. Unadjusted head CT ordering rates per physician ranged from 4.4% to 16.9% overall and from 15.2% to 61.7% in patients diagnosed with atraumatic headaches, with both rates varying significantly between physicians. Two-fold variation in head CT ordering overall (6.5%-13.5%) and approximately 3-fold variation in head CT ordering for atraumatic headaches (21.2%-60.1%) persisted even after controlling for pertinent variables. CONCLUSION Emergency physicians vary significantly in their use of head CT both overall and in patients with atraumatic headaches. Further studies are needed to identify strategies to reduce interphysician variation in head CT use.