Lipiodol as an intra-procedural imaging biomarker for liver tumor response to transarterial chemoembolization: Post-hoc analysis of a prospective clinical trial.

BACKGROUND: The use of the ethiodized oil- Lipiodol in conventional trans-arterial chemoembolization (cTACE) ensures radiopacity to visualize drug delivery in the process of providing selective drug targeting to hepatic cancers and arterial embolization. Lipiodol functions as a carrier of chemo drugs for targeted therapy, as an embolic agent, augmenting the drug effect by efflux into the portal veins as well as a predictor for the tumor response and survival. PURPOSE: To prospectively evaluate the role of 3D quantitative assessment of intra-procedural Lipiodol deposition in liver tumors on CBCT immediately after cTACE as a predictive biomarker for the outcome of cTACE. MATERIALS & METHODS: This was a post-hoc analysis of data from an IRB-approved prospective clinical trial. Thirty-two patients with hepatocellular carcinoma or liver metastases underwent contrast enhanced CBCT obtained immediately after cTACE, unenhanced MDCT at 24 h after cTACE, and follow-up imaging 30-, 90- and 180-days post-procedure. Lipiodol deposition was quantified on CBCT after cTACE and was characterized by 4 ordinal levels: ≤25%, >25-50%, >50-75%, >75%. Tumor response was assessed on follow-up MRI. Lipiodol deposition on imaging, correlation between Lipiodol deposition and tumor response criteria, and correlation between Lipiodol coverage and median overall survival (MOS) were evaluated. RESULTS: Image analysis demonstrated a high degree of agreement between the Lipiodol deposition on CBCT and the 24 h post-TACE CT, with a Bland-Altman plot of Lipiodol deposition on imaging demonstrated a bias of 2.75, with 95%-limits-of-agreement: -16.6 to 22.1%. An inverse relationship between Lipiodol deposition in responders versus non-responders for two-dimensional EASL reached statistical significance at 30 days (p = 0.02) and 90 days (p = 0.05). Comparing the Lipiodol deposition in Modified Response Evaluation Criteria in Solid Tumors (mRECIST) responders versus non-responders showed a statistically significant higher volumetric deposition in responders for European Association for the Study of the Liver (EASL)-30d, EASL-90d, and quantitative EASL-180d. The correlation between the relative Lipiodol deposition and the change in enhancing tumor volume showed a negative association post-cTACE (30-day: p < 0.001; rho = -0.63). A Kaplan-Meier analysis for patients with high vs. low Lipiodol deposition showed a MOS of 46 vs. 33 months (p = 0.05). CONCLUSION: 3D quantification of Lipiodol deposition on intra-procedural CBCT is a predictive biomarker of outcome in patients with primary or metastatic liver cancer undergoing cTACE. There are spatial and volumetric agreements between 3D quantification of Lipiodol deposition on intra-procedural CBCT and 24 h post-cTACE MDCT. The spatial and volumetric agreement between Lipiodol deposition on intra-procedural CBCT and 24 h post-cTACE MDCT could suggest that acquiring MDCT 24 h after cTACE is redundant. Importantly, the demonstrated relationship between levels of tumor coverage with Lipiodol and degree and timeline of tumor response after cTACE underline the role of Lipiodol as an intra-procedural surrogate for tumor response, with potential implications for the prediction of survival.

Intra-arterial therapies for liver cancer: assessing tumor response.

INTRODUCTION: Intra-arterial therapies (IATs) play an integral role in the management of unresectable hepatocellular carcinoma and liver metastases. The ability to accurately assess tumor response to intra-arterial therapies is crucial for clinical management. Several one- and two-dimensional manual imaging-based response assessment techniques, based both on tumor size or enhancement, have shown to be highly subjective and merely surrogate for the actual tumor as a whole. Areas covered: Given the currently existing literature, we will discuss all available tumor assessment techniques and criteria for liver cancer with a strong emphasis on 3D quantitative imaging biomarkers of tumor response in this review. Expert commentary: The growing role of information technology in medicine has brought about the advent of software-assisted, segmentation-based assessment techniques that address the outstanding issues of a subjective reader and provide for more accurate assessment techniques for the locally treated lesions. Three-dimensional quantitative tumor assessment techniques are superior to one- and two-dimensional measurements. This allows for treatment alterations and more precise targeting, potentially resulting in improved patient outcome.

Particle embolization for the treatment of life-threatening epistaxis in a left ventricular assist device patient.

While epistaxis is self-limiting in most cases, patients who are anticoagulated are at increased risk for life-threatening hemorrhage. The management of epistaxis in patients with a left ventricular assist device is further complicated by an increased risk for hemodynamic instability. Here, we detail the successful treatment of massive epistaxis in a left ventricular assist device patient by endovascular particle embolization. We hope to increase awareness in the cardiovascular community of this minimally invasive, potentially life-saving procedure.

MicroRNA expression profiling of oligodendrocyte differentiation from human embryonic stem cells.

BACKGROUND: Cells of the oligodendrocyte (OL) lineage play a vital role in the production and maintenance of myelin, a multilamellar membrane which allows for saltatory conduction along axons. These cells may provide immense therapeutic potential for lost sensory and motor function in demyelinating conditions, such as spinal cord injury, multiple sclerosis, and transverse myelitis. However, the molecular mechanisms controlling OL differentiation are largely unknown. MicroRNAs (miRNAs) are considered the "micromanagers" of gene expression with suggestive roles in cellular differentiation and maintenance. Although unique patterns of miRNA expression in various cell lineages have been characterized, this is the first report documenting their expression during oligodendrocyte maturation from human embryonic stem (hES) cells. Here, we performed a global miRNA analysis to reveal and identify characteristic patterns in the multiple stages leading to OL maturation from hES cells including those targeting factors involved in myelin production. METHODOLOGY/PRINCIPAL FINDINGS: We isolated cells from 8 stages of OL differentiation. Total RNA was subjected to miRNA profiling and validations preformed using real-time qRT-PCR. A comparison of miRNAs from our cultured OLs and OL progenitors showed significant similarities with published results from equivalent cells found in the rat and mouse central nervous system. Principal component analysis revealed four main clusters of miRNA expression corresponding to early, mid, and late progenitors, and mature OLs. These results were supported by correlation analyses between adjacent stages. Interestingly, the highest differentially-expressed miRNAs demonstrated a similar pattern of expression throughout all stages of differentiation, suggesting that they potentially regulate a common target or set of targets in this process. The predicted targets of these miRNAs include those with known or suspected roles in oligodendrocyte development and myelination including C11Orf9, CLDN11, MYTL1, MBOP, MPZL2, and DDR1. CONCLUSIONS/SIGNIFICANCE: We demonstrate miRNA profiles during distinct stages in oligodendroglial differentiation that may provide key markers of OL maturation. Our results reveal pronounced trends in miRNA expression and their potential mRNA target interactions that could provide valuable insight into the molecular mechanisms of differentiation.

Efficient differentiation of human embryonic stem cells into oligodendrocyte progenitors for application in a rat contusion model of spinal cord injury.

This study utilized a contusion model of spinal cord injury (SCI) in rats using the standardized NYU-MASCIS impactor, after which oligodendrocyte progenitor cells (OPCs) derived from human embryonic stem cell (ESC) were transplanted into the spinal cord to study their survival and migration route toward the areas of injury. One critical aspect of successful cell-based SCI therapy is the time of injection following injury. OPCs were injected at two clinically relevant times when most damage occurs to the surrounding tissue, 3 and 24 hours following injury. Migration and survivability after eight days was measured postmortem. In-vitro immunofluorescence revealed that most ESC-derived OPCs expressed oligodendrocyte markers, including CNPase, GalC, Olig1, O4, and O1. Results showed that OPCs survived when injected at the center of injury and migrated away from the injection sites after one week. Histological sections revealed integration of ESC-derived OPCs into the spinal cord with contusion injury without disruption to the parenchyma. Cells survived for a minimum of eight days after injury, without tumor or cyst formation. The extent of injury and effect of early cell transplant was measured using behavioral and electrophysiological assessments which demonstrated increased neurological responses in rats transplanted with OPCs compared to controls.