Genomic sequencing in clinical trials

Human genome sequencing is the process by which the exact order of nucleic acid base pairs in the 24 human chromosomes is determined. Since the completion of the Human Genome Project in 2003, genomic sequencing is rapidly becoming a major part of our translational research efforts to understand and improve human health and disease. This article reviews the current and future directions of clinical research with respect to genomic sequencing, a technology that is just beginning to find its way into clinical trials both nationally and worldwide. We highlight the currently available types of genomic sequencing platforms, outline the advantages and disadvantages of each, and compare first- and next-generation techniques with respect to capabilities, quality, and cost. We describe the current geographical distributions and types of disease conditions in which these technologies are used, and how next-generation sequencing is strategically being incorporated into new and existing studies. Lastly, recent major breakthroughs and the ongoing challenges of using genomic sequencing in clinical research are discussed

The Role of Percutaneous Image-Guided Thermal Ablation for the Treatment of Pulmonary Malignancies

OBJECTIVE. Image-guided thermal ablation is a minimally invasive treatment option for patients with primary and secondary pulmonary malignancies. Modalities include radio-frequency ablation, microwave ablation, and cryoablation.CONCLUSION. Although no large randomized studies exist comparing ablation to surgery or radiotherapy, numerous studies have reported safety and efficacy for the treatment of both primary and metastatic disease in select patients. Future studies will refine patient selection, procedural technique, and assessment for local recurrence and will evaluate long-term survival.</p

Intraprocedural Transcatheter Intraarterial Perfusion (TRIP)-MRI for Evaluation of Irreversible Electroporation Therapy Response in a Rabbit Liver Tumor Model.

PurposeIrreversible electroporation (IRE) is a promising new ablation method for hepatocellular carcinoma (HCC) treatment with few side-effects; however, tissue perfusion and differentiation between treatment zones have not been sufficiently studied. In this project, we analyzed HCC tumor perfusion changes immediately after IRE treatment using transcatheter intraarterial perfusion (TRIP)-MRI to monitor treatment zone margins.Materials and methodsAll protocols were approved by the institutional animal care and use committee. A total of 34 rabbits were used for this prospective study: tumor liver group (n=17), normal liver group (n=14), and 3 for growing VX2 tumors. All procedures and imaging were performed under anesthesia. VX2 tumors were grown by injection of VX2 cells into rabbit hindlimbs. Liver tumors were induced by percutaneous US-guided injection of VX2 tumor fragments into liver. For digital subtraction angiography (DSA), a 2F catheter was advanced through left hepatic artery via femoral artery access, followed by contrast injection. All rabbits underwent baseline anatomic MRI, then IRE procedure or IRE probe placement only, and lastly post-procedure anatomic and TRIP-MRI. Liver tissues were dissected immediately after imaging for histology. All statistical analyses were performed on GraphPad Prism, with P&lt;0.05 considered significant.ResultsIRE generated central IRE zone and peripheral reversible electroporation (RE) zone on anatomic MRI for both normal liver and liver tumor tissues. The semiquantitative analysis showed that IRE zone had the lowest AUC, PE, WIS, Ktrans, ve , and vp as well as the highest TTP, followed by RE zone, then untreated tissues. Receiver operating characteristic analysis showed that WIS and AUC60 had the highest AUCROC. Histologic analysis showed a positive correlation in viable area fraction between MRI and histologic measurements. IRE zone had the highest %apoptosis and lowest CD31+ staining.ConclusionOur results demonstrated that intraprocedural TRIP-MRI can effectively differentiate IRE and RE zones after IRE ablation in normal liver and liver tumor tissues

Yttrium-90 Portal Vein Radioembolization in Sprague-Dawley Rats: Dose-Dependent Imaging and Pathological Changes in Normal Liver.

PurposePortal vein embolization (PVE) is an established neoadjuvant method to induce future liver remnant hypertrophy prior to surgical resection of hepatic tumors. The purpose of our study was to examine the feasibility of PVE with glass 90Y microspheres (Y90 PVE) in Sprague-Dawley rats. We tested the hypothesis that increased doses of Y90 PVE would increase target lobe fibrosis and atrophy.MethodsTwenty-two rats were assigned to four groups for Y90 PVE to the right median lobe: very high- (273.8&nbsp;MBq; n = 2), high- (99.9&nbsp;MBq; n = 10), medium- (48.1&nbsp;MBq; n = 5), and low-dose (14.8&nbsp;MBq; n = 5). An untreated control group included seven rats. 90Y PET/CT of 90Y distributions confirmed lobar targeting. MRI volumes were measured at baseline, 2-, 4-, 8- and 12-weeks. Explanted hepatic lobes were weighed, sectioned, and stained for H&amp;E and immunohistochemistry. Digitized slides allowed quantitative measurements of fibrosis (20 foci/slide).ResultsEx vivo measurements confirmed 91-97% activity was localized to the target lobe (n = 4). The percent growth of the target lobe relative to baseline was -&nbsp;5.0% (95% CI -&nbsp;17.0-6.9%) for high-, medium dose rats compared to + 18.6% (95% CI + 7.6-29.7%) in the low-dose group at 12-weeks (p = 0.0043). Radiation fibrosis increased in a dose-dependent fashion. Fibrotic area/microsphere was 22,893.5, 14,946.2 ± 2253.3, 15,304.5 ± 4716.6, and 5268.8 ± 2297.2&nbsp;μm2 for very high- (n = 1), high- (n = 4), medium- (n = 3), and low-dose groups (n = 5), respectively.ConclusionY90 PVE was feasible in the rat model, resulted in target lobe atrophy, and dose-dependent increases in hepatic fibrosis at 12&nbsp;weeks. The onset of imaging-based volumetric changes was 8-12&nbsp;weeks

Correlation and Agreement of Yttrium-90 Positron Emission Tomography/Computed Tomography with Ex&nbsp;Vivo Radioembolization Microsphere Deposition in the Rabbit VX2 Liver Tumor Model

PurposeTo demonstrate a stronger correlation and agreement of yttrium-90 (90Y) positron emission tomography (PET)/computed tomography (CT) measurements with explant liver tumor dosing compared with the standard model (SM) for radioembolization.Materials and methodsHepatic VX2 tumors were implanted into New Zealand white rabbits, with growth confirmed by 7 T magnetic resonance imaging. Seventeen VX2 rabbits provided 33 analyzed tumors. Treatment volumes were calculated from manually drawn volumes of interest (VOI) with three-dimensional surface renderings. Radioembolization was performed with glass 90Y microspheres. PET/CT imaging was completed with scatter and attenuation correction. Three-dimensional ellipsoid VOI were drawn to encompass tumors on fused images. Tumors and livers were then explanted for inductively coupled plasma (ICP)-optical emission spectroscopy (OES) analysis of microsphere content. 90Y PET/CT and SM measurements were compared with reference standard ICP-OES measurements of tumor dosing with Pearson correlation and Bland-Altman analyses for agreement testing with and without adjustment for tumor necrosis.ResultsThe median infused activity was 33.3 MBq (range, 5.9-152.9). Tumor dose was significantly correlated with 90Y PET/CT measurements (r&nbsp;= 0.903, P &lt; .001) and SM estimates (r&nbsp;= 0.607, P &lt; .001). Bland-Altman analyses showed that the SM tended to underestimate the tumor dosing by a mean of&nbsp;-8.5 Gy (CI,&nbsp;-26.3-9.3), and the degree of underestimation increased to a mean of&nbsp;-18.3 Gy (CI,&nbsp;-38.5-1.9) after the adjustment for tumor necrosis.Conclusions90Y PET/CT estimates were strongly correlated and had better agreement with reference measurements of tumor dosing than SM estimates