Morphometric evaluation of traumatic axonal injury and the correlation with post-traumatic cerebral atrophy and functional outcome.

INTRODUCTION: Imaging plays a crucial role in the diagnosis, prognosis and follow-up of traumatic brain injury. Whereas computed tomography plays a pivotal role in the acute setting, magnetic resonance imaging is best suited to detect the true extent of traumatic brain injury, and more specifically diffuse axonal injury. Post-traumatic brain atrophy is a well-known complication of traumatic brain injury. PURPOSE: This study investigated the correlation between diffuse axonal injury detected with fluid-attenuated inversion recovery and susceptibility-weighted imaging magnetic resonance imaging, post-traumatic brain atrophy and functional outcome (Glasgow outcome scale - extended). MATERIALS AND METHODS: Twenty patients with a closed head injury and diffuse axonal injury detected with fluid-attenuated inversion recovery and susceptibility-weighted imaging were included. The total volumes of the diffuse axonal injury fluid-attenuated inversion recovery lesions were determined for each subject's initial (<14 days) and follow-up magnetic resonance scan (average: day 303 ± 83 standard deviation). The different brain volumes were automatically quantified using a validated and both US Food and Drug Administration-cleared and CE-marked machine learning algorithm (icobrain). The number of susceptibility-weighted imaging lesions and functional outcome scores (Glasgow outcome scale - extended) were retrieved from the Collaborative European NeuroTrauma Effectiveness Research Traumatic Brain Injury dataset. RESULTS: The volumetric fluid-attenuated inversion recovery diffuse axonal injury lesion load showed a significant inverse correlation with functional outcome (Glasgow outcome scale - extended) (r = -0.57; P = 0.0094) and white matter volume change (r = -0.50; P = 0.027). In addition, white matter volume change correlated significantly with the Glasgow outcome scale - extended score (P = 0.0072; r = 0.58). Moreover, there was a strong inverse correlation between longitudinal fluid-attenuated inversion recovery lesion volume change and whole brain volume change (r = -0.63; P = 0.0028). No significant correlation existed between the number of diffuse axonal injury susceptibility-weighted imaging lesions, brain atrophy and functional outcome. CONCLUSIONS: Volumetric analysis of diffuse axonal injury on fluid-attenuated inversion recovery imaging and automated brain atrophy calculation are potentially useful tools in the clinical management and follow-up of traumatic brain injury patients with diffuse axonal injury.

Micro-HCCs in rats with liver cirrhosis: paradoxical targeting effects with vascular disrupting agent CA4P.

We sought to investigate anticancer efficacy of a vascular disrupting agent (VDA) combretastatin A-4 phosphate (CA4P) in relation to tumor size among hepatocellular carcinomas (HCCs) in rats using magnetic resonance imaging (MRI) and postmortem techniques. Nineteen rats with 43 chemically-induced HCCs of 2.8-20.9 mm in size on liver cirrhosis received CA4P intravenously at 10 mg/kg. Tumor-diameter was measured by T2-weighted imaging (T2WI) to define microcancers (< 5 mm) versus larger HCCs. Vascular responses and tissue necrosis were detected by diffusion-weighted imaging (DWI), contrast-enhanced T1-weighted imaging (CE-T1WI) and dynamic contrast enhanced (DCE-) MRI, which were validated by microangiography and histopathology. MRI revealed nearly complete necrosis in 5 out of 7 micro-HCCs, but diverse therapeutic necrosis in larger HCCs with a positive correlation with tumor size. Necrosis in micro-HCCs was 36.9% more than that in larger HCCs. While increased diffusion coefficient (ADCdiff) suggested tumor necrosis, perfusion coefficient (ADCperf) indicated sharply decreased blood perfusion in cirrhotic liver together with a reduction in micro-HCCs. DCE revealed lowered tumor blood flow from intravascular into extravascular extracellular space (EES). Microangiography and histopathology revealed hypo- and hypervascularity in 4 and 3 micro-HCCs, massive, partial and minor degrees of tumoral necrosis in 5, 1 and 1 micro-HCCs respectively, and patchy necrotic foci in cirrhotic liver. CD34-PAS staining implicated that poorly vascularized micro-HCCs growing on liver cirrhosis tended to respond better to CA4P treatment. In this study, more complete CA4P-response occurred unexpectedly in micro-HCCs in rats, along with CA4P-induced necrotic foci in cirrhotic liver. These may help to plan clinical applications of VDAs in patients with HCCs and liver cirrhosis.

Comparison of two vascular-disrupting agents at a clinically relevant dose in rodent liver tumors with multiparametric magnetic resonance imaging biomarkers.

We sought to compare the therapeutic efficacy between two vascular-disrupting agents, combretastatin A4 phosphate (CA4P) and ZD6126, at a clinically relevant dose on tumor models with magnetic resonance imaging (MRI). Thirty rats with liver rhabdomyosarcoma were randomized into CA4P (10 mg/kg), ZD6126 (10 mg/kg), and control group (n=10 for each group). Multiparametric MRI biomarkers including tumor volume, enhancement ratio, necrosis ratio, apparent diffusion coefficient (ADC), and K (volume transfer constant) derived from T2-weighted, T1-weighted, contrast-enhanced T1-weighted, and diffusion-weighted imaging, and dynamic contrast-enhanced MRI were compared at pretreatment, 1 h, 6 h, 24 h, 48 h, and 120 h posttreatment; they were validated using ex-vivo techniques. Relative to rapidly growing tumors without necrosis in control rats, tumors grew slower in the CA4P group compared with the ZD6126 group with a higher necrosis ratio at 120 h (P<0.05), as proven by histopathology. In the CA4P group, K decreased from 1 h until 6 h, and partially recovered at 120 h. In the ZD6126 group, the reduced K at 1 h began to rebound from 6 h and exceeded the baseline value at 120 h (P<0.05), parallel to evolving enhancement ratios (P<0.05). ADC revealed more necrotic tumors with CA4P versus ZD6126 at 120 h (P<0.05). The different tumor responses were confirmed by ex-vivo microangiography and histopathology. CA4P was more effective than ZD6126 in impairing blood supply, inducing necrosis, and delaying growth in rat liver tumors at a clinically relevant dose. A single dose of vascular-disrupting agent was insufficient to destroy the tumor. The multiparametric MRI biomarkers enabled in-vivo noninvasive comparison of therapeutic efficacy between CA4P and ZD6126.