Jadranka Stojanovska

Diffusion imaging for evaluation of tumor therapies in preclinical animal models

The increasing development of novel targeted therapies for treating solid tumors has necessitated the development of technology to determine their efficacy in preclinical animal models. One such technology that can non-invasively quantify early changes in tumor cellularity as a result of an efficacious therapy is diffusion MRI. In this overview we present some theories as to the origin of diffusion changes as a result of tumor therapy, a robust methodology for acquisition of apparent diffusion coefficient maps and some applications of determining therapeutic efficacy in a variety therapeutic regimens and animal models.

Therapeutic Efficacy of DTI-015 using Diffusion Magnetic Resonance Imaging as an Early Surrogate Marker

To investigate diffusion weighted magnetic resonance imaging as a quantitative surrogate marker for evaluating the therapy-induced cellular changes in an orthotopic experimental glioma model, tumors were treated with direct intratumoral administration of DTI-015, a solution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in 100% EtOH. Intracerebral 9L tumors were induced in Fischer 344 rats, and three treatment groups were established: DTI-015, EtOH, and sham. Two groups of rats received intratumoral injection of either 67 mg/mL BCNU in EtOH or EtOH alone at 50% of the tumor volume up to a maximum of 30 μl under stereotactic guidance. Diffusion magnetic resonance images were acquired before treatment and after treatment at 1, 24, 48, and 72 hours and then 3 times per week thereafter. Tumor cell viability was examined using multislice diffusion weighted magnetic resonance imaging with diffusion weighted transverse magnetic resonance images and histogram plots of each tumor quantified over time. Control animals (EtOH- or sham-treated animals) showed mean apparent diffusion coefficients (ADCs) that remained essentially unchanged over the experimental time course. In contrast, rats treated with DTI-015 showed a significant increase in ADC relative to the pretreatment within 24 hours, which further increased over time, followed by a significant therapeutic response as evidenced by subsequent tumor volume shrinkage, development of a cystic region, and enhanced animal survival. Finally, not only were ADC measurements predictive of differences between treatment groups, but they also yielded spatial and temporal data regarding the efficacy of treatment within individual treated animals that could be used to guide subsequent therapy.

Impact of mitral isthmus anatomy on the likelihood of achieving linear block in patients undergoing catheter ablation of persistent atrial fibrillation

BACKGROUND Although prior studies have described the anatomy of the mitral isthmus in patients undergoing left atrial (LA) ablation of atrial fibrillation (AF), none has examined the impact of isthmus anatomy on the likelihood of achieving conduction block. OBJECTIVE The purpose of this study was to identify morphologic characteristics of the mitral isthmus that may influence the acute efficacy of linear ablation at the mitral isthmus. METHODS Fifty-five patients (age 61 ± 10 years, 41 [75%] men, LA 46 ± 6 mm, ejection fraction 0.55 ± 0.11, AF duration 4 ± 3 years) underwent linear ablation at the mitral isthmus during an ablation procedure for persistent AF. Computed tomographic scan was performed before the procedure. The morphology of the mitral isthmus and its anatomic relationship to the adjacent vasculature were analyzed. RESULTS Complete block along the mitral isthmus was achieved in 35 (64%) of 55 patients, 23 (66%) of whom required radiofrequency ablation in the coronary sinus (CS). Patients with incomplete block were more likely to have a pouch at the isthmus (40% vs 9%; P = .01), a greater isthmus depth (8.1 ± 4.2 mm vs 5.7 ± 3.4 mm; P = .04), and a higher prevalence of an interposed circumflex artery between the CS and the mitral isthmus (60% vs 20%; P = .003) compared to patients with isthmus block. An interposed circumflex artery was the only independent predictor of incomplete conduction block at the mitral isthmus (odds ratio 4.9, 95% confidence interval 1.3-18.2; P = .02). CONCLUSION Preprocedural computed tomographic imaging identifies patients in whom linear ablation at the mitral isthmus is unlikely to be successful. Interposition of the circumflex artery between the mitral isthmus and the CS is associated with a lower probability of achieving complete mitral isthmus block.

Sodium magnetic resonance imaging of chemotherapeutic response in a rat glioma

This study investigates the comparative changes in the sodium MRI signal and proton diffusion following treatment using a 9L rat glioma model to develop markers of earliest response to cancer therapy. Sodium MRI and proton diffusion mapping were performed on untreated (n = 5) and chemotherapy 1,3‐bis(2‐chloroethyl)‐1‐nitrosourea‐treated rats (n = 5). Animals were scanned serially at 2‐ to 3‐day intervals for up to 30 days following therapy. The time course of Na concentration in a tumor showed a dramatic increase in the treated brain tumor compared to the untreated tumor, which correlates in time with an increase in tumor water diffusion. The largest posttreatment increase in sodium signal occurred 7–9 days following treatment and correlated to the period of the greatest chemotherapy‐induced cellular necrosis based on diffusion and histopathology. Both Na MRI and proton ADC mapping revealed early changes in tumor sodium content and cellularity. This study demonstrates the possibility of Na MRI to function as a biomarker for monitoring early tumor treatment and validates the use of monitoring changes in diffusion MRI values for assessing tumor cellularity. Magn Reson Med 53:85–92, 2005.

Inhibition of vascular endothelial growth factor (VEGF)-A causes a paradoxical increase in tumor blood flow and up-regulation of VEGF-D.

Purpose: Vascular endothelial growth factor (VEGF)-A is an important mediator of angiogenesis in almost all solid tumors. The aim of this study was to evaluate the effect of VEGF-A expression on tumor growth, perfusion, and chemotherapeutic efficacy in orthotopic 9L gliosarcomas. Experimental Design: Stable 9L cell lines underexpressing and overexpressing VEGF-A were generated. Anatomic, susceptibility contrast, and continuous arterial spin-labeling magnetic resonance imaging were used to quantify the volume, blood volume, and blood flow of tumors orthotopically grown from these and wild-type 9L cells. Histologic, immunohistochemical, and quantitative reverse transcription-PCR analyses were also done on excised tumors. Finally, the effects of carmustine chemotherapy were also evaluated. Results: Orthotopic tumors underexpressing VEGF-A had slower growth rates (increased median survival), greater blood flow, vessel density, and VEGF-D expression, but no statistical difference in blood volume and chemotherapeutic sensitivity, compared with tumors with wild-type levels of VEGF-A. Tumors overexpressing VEGF-A had faster growth rates, greater blood volume, vessel density, and blood flow but no statistical difference in VEGF-D expression and chemotherapeutic sensitivity compared with wild-type VEGF-A-expressing tumors. Conclusion: Blood volume and blood flow are independent and different biomarkers of tumor perfusion. Therefore, both should be measured when characterizing the efficacy of antiangiogenic therapies. Underexpression of VEGF-A does not result in complete inhibition of angiogenesis. Moreover, these tumors have a different perfusion phenotype, suggesting that angiogenesis is mediated by an alternative pathway. The results indicate that VEGF-D is a plausible alternative mediator of this angiogenesis.

Embryology and imaging review of aortic arch anomalies

Congenital malformations of the thoracic aorta can be discovered on chest radiographs when associated with symptoms or found incidentally. We review the imaging anatomy and associations of many of the aortic arch malformations that can be encountered in adults and highlight key points with regard to their treatment and prognoses. An understanding of the normal and abnormal embryologic development of the aortic arch, with knowledge of their imaging features, may be important for improving diagnostic accuracy and patient care.

Pilot Study of Cardiac Magnetic Resonance Imaging for Detection of Embolic Source After Ischemic Stroke

BACKGROUND Transesophageal echocardiography (TEE) is the standard for evaluating cardioembolic sources of stroke, although many strokes remain cryptogenic after TEE. Cardiac magnetic resonance (CMR) imaging may have advantages over TEE. We performed a prospective pilot study comparing CMR to TEE after stroke to assist in planning future definitive studies. METHODS Individuals with nonlacunar stroke within 90 days of undergoing clinical TEE were prospectively identified and underwent a 1.5 Tesla research CMR scan. Exclusion criteria included >50% relevant cervical vessel stenosis and inability to undergo nonsedated CMR. A descriptive comparison of cardioembolic source (intracardiac thrombus/mass, aortic atheroma ≥ 4 mm, or patent foramen ovale [PFO]) by study type was performed. RESULTS Twenty patients underwent CMR and TEE a median of 6 days apart. The median age was 51 years (interquartile range [IQR] 40, 63.5), 40% had hypertension, 15% had diabetes, 25% had a previous stroke/transient ischemic attack, 5% had atrial fibrillation, and none had coronary disease or heart failure. No patient had intracardiac thrombus or mass detected on either study. Aortic atheroma ≥ 4 mm thick was identified by TEE in 1 patient. CMR identified aortic atheroma as <4 mm in this patient (3 mm on CMR compared with 5 mm on TEE). PFO was identified in 6 of 20 patients on TEE; CMR found only 1 of these. CONCLUSIONS In this pilot study, TEE identified more potential cardioembolic sources than CMR imaging. Future studies comparing TEE and CMR after stroke should focus on older subjects at higher risk for cardiac disease to determine whether TEE, CMR, or both can best elucidate potential cardioembolic sources.

Reference Normal Absolute and Indexed Values From ECG-Gated MDCT: Left Atrial Volume, Function, and Diameter

OBJECTIVE The purpose of this study was to retrospectively determine CT-based normal reference values of left atrial volume, function, and diameter normalized by age, sex, and body surface area. MATERIALS AND METHODS The study group consisted of 74 subjects with normal findings at ECG-gated coronary CT angiography performed with retrospective gating. Analysis of left atrial volume (end-diastolic, end-systolic, and stroke volume) and function (ejection fraction) was performed with the Simpson method. Left atrial diameter was measured in the anteroposterior dimension. General linear model analysis was performed to model the data and assess statistical significance by age group after adjustment for sex and body surface area. RESULTS The reference range for left atrial volume, function, and diameter was normalized (indexed) to age, sex, and body surface area in healthy subjects. A statistically significant difference was noted between left atrial volume and age without adjustment for sex and body surface area, but no statistically significant difference was found after adjustment for these variables. Sex and body surface area had a significant influence on left atrial volume, function, and diameter. CONCLUSION Left atrial volume, function, and diameter normalized to age, sex, and body surface area can be reported from CTA datasets and may provide information important for patient care.

Magnetic resonance imaging in patients with cardiac implanted electronic devices: focus on contraindications to magnetic resonance imaging protocols

Aims Magnetic resonance imaging (MRI) has been reported to be safe in patients with cardiac implantable electronic devices (CIED) provided a specific protocol is followed. The objective of this study was to assess whether this is also true for patients excluded from published protocols. Methods and results A total of 160 MRIs were obtained in 142 consecutive patients with CIEDs [106 patients had an implantable cardioverter defibrillator (ICD) and 36 had a pacemaker implanted] using an adapted, pre-specified protocol. A cardiac MRI was performed in 95 patients, and a spinal/brain MRI was performed in 47 patients. Forty-six patients (32%) had either abandoned leads (n = 10), and/or were pacemaker dependent with an implanted ICD (n = 19), had recently implanted CIEDs (n = 1), and/or had a CIED device with battery depletion (n = 2), and/or a component of the CIED was recalled or on advisory (n = 32). No major complications occurred. Some device parameters changed slightly, but significantly, right after or at 1-week post-MRI without requiring any reprogramming. In one patient with an ICD on advisory, the pacing rate changed inexplicably during one of his two MRIs from 90 to 50 b.p.m. Conclusion Using a pre-specified protocol, cardiac and non-cardiac MRIs were performed in CIED patients with pacemaker dependency, abandoned leads, or depleted batteries without occurrence of major adverse events. Patients with devices on advisory need to be monitored carefully during MRI, especially if they are pacemaker dependent.

Congenital and Hereditary Causes of Sudden Cardiac Death in Young Adults: Diagnosis, Differential Diagnosis, and Risk Stratification

Sudden cardiac death is defined as death from unexpected circulatory arrest-usually a result of cardiac arrhythmia-that occurs within 1 hour of the onset of symptoms. Proper and timely identification of individuals at risk for sudden cardiac death and the diagnosis of its predisposing conditions are vital. A careful history and physical examination, in addition to electrocardiography and cardiac imaging, are essential to identify conditions associated with sudden cardiac death. Among young adults (18-35 years), sudden cardiac death most commonly results from a previously undiagnosed congenital or hereditary condition, such as coronary artery anomalies and inherited cardiomyopathies (eg, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy [ARVC], dilated cardiomyopathy, and noncompaction cardiomyopathy). Overall, the most common causes of sudden cardiac death in young adults are, in descending order of frequency, hypertrophic cardiomyopathy, coronary artery anomalies with an interarterial or intramural course, and ARVC. Often, sudden cardiac death is precipitated by ventricular tachycardia or fibrillation and may be prevented with an implantable cardioverter defibrillator (ICD). Risk stratification to determine the need for an ICD is challenging and involves imaging, particularly echocardiography and cardiac magnetic resonance (MR) imaging. Coronary artery anomalies, a diverse group of congenital disorders with a variable manifestation, may be depicted at coronary computed tomographic angiography or MR angiography. A thorough understanding of clinical risk stratification, imaging features, and complementary diagnostic tools for the evaluation of cardiac disorders that may lead to sudden cardiac death is essential to effectively use imaging to guide diagnosis and therapy.