Percutaneous CT-Guided Cryoneurolysis of the Intercostobrachial Nerve for Management of Postmastectomy Pain Syndrome.

PURPOSE: To evaluate the feasibility, safety, and efficacy of intercostobrachial nerve (ICBN) cryoneurolysis for pain control in patients with postmastectomy pain syndrome (PMPS). MATERIALS AND METHODS: Fourteen patients with PMPS were prospectively enrolled into this clinical trial after a positive response to a diagnostic computed tomography (CT)-guided percutaneous block of the ICBN. Participants subsequently underwent CT-guided percutaneous cryoneurolysis of the same nerve and were observed on postprocedural Days 10, 90, and 180. Pain scores, quality-of-life measurements, and global impression of change values were recorded before the procedure and at each follow-up point using established validated outcome instruments. RESULTS: Cryoneurolysis of the ICBN was technically successful in all 14 patients. The mean pain decreased significantly by 2.1 points at 10 days (P = .0451), by 2.4 points at 90 days (P = .0084), and by 2.9 points at 180 days (P = .0028) after cryoneurolysis. Pain interference with daily activities decreased significantly by 14.4 points after 10 days (P = .0161), by 16.2 points after 90 days (P = .0071), and by 20.7 points after 180 days (P = .0007). There were no procedure-related adverse events. CONCLUSIONS: Cryoneurolysis of the ICBN in patients with PMPS was technically feasible and safe and resulted in a significant decrease in postmastectomy pain for up to 6 months in this small cohort.

Percutaneous CT-Guided Cryovagotomy in Patients with Class I or Class II Obesity: A Pilot Trial.

OBJECTIVE: This study evaluated the safety of percutaneous CT-guided cryoablation of the vagus nerve (percutaneous cryovagotomy) in participants with class I or class II obesity. METHODS: The study was an open-label, single-group, prospective pilot investigation designed around safety-related stopping criteria. Twenty participants with 30 > BMI > 37 underwent percutaneous cryovagotomy with follow-up visits at day 7, 45, 90, and 180. Data related to adverse events, technical success, weight loss, quality of life, dietary intake, global impressions of hunger change, activity, and body composition were analyzed. RESULTS: The procedural technical success rate was 100%. There were no adverse events in 19 participants who completed the trial. Ninety-five percent of patients reported decreased appetite following the procedure, and reductions in mean absolute weight and BMI were observed at all time points. The mean quality of life and activity scores improved from baseline to 6 months post procedure, and mean caloric intake and overall body fat decreased over the same period. CONCLUSIONS: Percutaneous CT-guided cryovagotomy is feasible and was tolerated without complications or adverse events in this cohort. Quantitative preliminary data from this pilot investigation inform the design of a larger prospective randomized clinical trial.

Access to Interventional Radiology Services in Small Hospitals and Rural Communities: An ACR Membership Intercommission Survey.

PURPOSE: To evaluate the status of interventional radiology (IR) staffing, recruitment, and retention in the United States, specifically as they apply to small hospitals and rural communities. MATERIALS AND METHODS: A 22-question survey was created by an ACR intercommission workgroup and circulated via e-mail to ACR members who self-identified as a "group practice leader," "general radiologist," "interventional radiologist," or "abdominal radiologist." Contingency tables were constructed, and bivariate analyses were performed to assess overall responses and the distribution of responses among specific groups of respondents. RESULTS: A total of 1,005 e-mail recipients completed the survey. A statistically significant greater proportion of responders from rural hospitals (versus nonrural hospitals) answered that (1) their group falls short or far short of meeting demand for IR services (29.1% versus 14.3%), (2) they had difficulty recruiting IR physicians to their practice (67% versus 40.6%), and (3) they had difficulty retaining IR physicians (40% versus 29%). The most frequently reported reasons for difficulty recruiting were that IR-trained physicians "do not want to do diagnostic work" (56.2%) and "do not want to practice in a small or rural setting" (48.8%). A greater proportion of respondents from rural hospitals perceived that they had difficulty retaining IR physicians because of perceived inadequate "complexity of case mix" (67.5%) or "number of cases" (66.1%). CONCLUSION: Small hospitals and rural communities experience greater difficulty recruiting and retaining IR physicians and meeting IR service demands compared with their nonrural counterparts.

Percutaneous Image-Guided Cryoablation for the Treatment of Phantom Limb Pain in Amputees: A Pilot Study.

PURPOSE: To prospectively evaluate percutaneous image-guided nerve cryoablation for treatment of refractory phantom limb pain (PLP) in a pilot cohort for purposes of deriving parameters to design a larger, randomized, parallel-armed, controlled trial. MATERIALS AND METHODS: From January 2015 to January 2016, 21 patients with refractory PLP underwent image-guided percutaneous cryoneurolysis procedures. Visual analog scale scores were documented at baseline and 7, 45, and 180 days after the procedure. Responses to a modified Roland Morris Disability Questionnaire were documented at baseline and 7 and 45 days after the procedure. RESULTS: Technical success rate of the procedures was 100%. There were 6 (29%) minor procedure-related complications. Disability scores decreased from a baseline mean of 11.3 to 3.3 at 45-day follow-up (95% confidence interval 5.8, 10.3; P < .0001). Pain intensity scores decreased from a baseline mean of 6.2 to 2.0 at long-term follow-up (95% confidence interval 2.8, 5.6; P < .0001). CONCLUSIONS: Image-guided percutaneous nerve cryoablation is feasible and safe and may represent a new efficacious therapeutic option for patients with phantom pains related to limb loss.

Percutaneous CT-guided cryoablation for the treatment of refractory pudendal neuralgia.

PURPOSE: To evaluate the safety and efficacy of percutaneous CT-guided cryoablation of the pudendal nerve for the treatment of refractory pudendal neuralgia. MATERIALS AND METHODS: Eleven patients were selected to undergo percutaneous CT-guided cryoablation of the pudendal nerve based on established diagnostic criteria. Brief Pain Inventory questionnaires were administered prior to the procedure, during the immediate 24 h post procedure, and 45 days and 6 months following the procedure. RESULTS: Prior to treatment, the average level of pain on a scale from 0 (no pain) to 10 (worst pain imaginable) was 7.6, with pain described as "burning" (80%), "pulling" (37.5%), "crushing" (50%), "pressure" (84.5%), "throbbing" (50%), "knife-life" (52%), and "other" (60%). At 24 h, 45 days, and 6 months post-treatment, pain intensity dropped to 2.6, 3.5, and 3.1, respectively (p < 0.005). There were no procedure-related complications. CONCLUSIONS: CT-guided percutaneous cryoablation may represent a safe and efficacious option for selected patients with refractory pudendal neuralgia.

Image-guided cryoablation for the treatment of painful musculoskeletal metastatic disease: a single-center experience.

PURPOSE: The role of image-guided thermal ablation techniques for the nonoperative local management of painful osseous metastatic disease has expanded during recent years, and several advantages of cryoablation in this setting have emerged. The purpose of this study is to retrospectively evaluate and report a single-center experience of CT-guided percutaneous cryoablation in the setting of painful musculoskeletal metastatic disease. METHODS: This study was approved by the institutional review board and is compliant with the Health Insurance Portability and Accountability Act. Electronic medical records of all patients who underwent percutaneous image-guided palliative cryoablation at our institution were reviewed (n = 61). An intent-to-treat analysis was performed. Records were reviewed for demographic data and anatomical data, primary tumor type, procedure details, and outcome-including change in analgesic requirements (expressed as morphine equivalent dosages), pain scores (utilizing the clinically implemented visual analog scale), subsequent therapies (including radiation and/or surgery), and complications during the 24 h following the procedure and at 3 months. Patients were excluded (n = 7) if data were not retrospectively identifiable at the defined time points. RESULTS: Fifty-four tumors were ablated in 50 patients. There were statistically significant decreases in the median VAS score and narcotic usage at both 24 h and 3 months (p < 0.000). Six patients (11%) incurred complications related to their therapy. Two patients had no relief at 24 h, of which both reported worsened pain at 3 months. One patient had initial relief but symptom recurrence at 3 months. Four patients went on to have radiation therapy of the ablation site at some point following the procedure. CONCLUSIONS: CT-guided cryoablation is a safe, effective, reproducible procedural option for the nonoperative local treatment of painful musculoskeletal metastatic disease.

Incidence of hypercoagulable events after image-guided percutaneous cryoablation of renal tumors: a single-center experience.

PURPOSE: To identify retrospectively hypercoagulable events that occurred over time in patients who underwent image-guided percutaneous renal cryoablation and compare the incidence with a cohort of patients who underwent surgical partial nephrectomy (PN) during the same time period. MATERIALS AND METHODS: An electronic medical record database was queried for patients who underwent percutaneous image-guided renal mass cryoablation or PN between September 2006 and June 2012. Records were examined for thrombotic events during the year following the procedure in each group. Incidence rates, Kaplan-Meier estimates, and patient demographic variables were compared using the stratified log-rank test and t test for independent samples. RESULTS: The study comprised 114 cryoablation cases. The cumulative incidence of thrombotic events after 1 year was 4.39%. The incidence per 100 person-years was 4.84. There were 105 PN cases. The cumulative incidence of thrombotic events after 1 year was 1.0%. The incidence per 100 person-years was 1.14. The person-time incidence rate difference for these two groups did not reach statistical significance (P = .0894). CONCLUSIONS: The incidence of thrombotic events in patients who underwent percutaneous renal cryoablation in this study was not significantly different than a comparable cohort who underwent surgical PN during the same time period.

In vitro characterization of uptake mechanism of L-[methyl-(3)H]-methionine in hepatocellular carcinoma.

PURPOSE: Methionine (Met) could be a useful imaging biomarker for the diagnosis of hepatocellular carcinoma (HCC), as demonstrated by PET imaging with L-[methyl-(11)C]-Met. In HCC cells, protein synthesis mainly contributes to radiopharmaceutical uptake. In contrast, lipid synthesis via the phosphatidylethanolamine (PE) methylation pathway is the major metabolic route of L-[methyl-(11)C]-Met in normal hepatocytes, which contributes to the background contrast observed in PET images. However, the mechanisms of amino acid transport and the roles of the two key enzymes, methionine adenosyltransferase (MAT) and phosphatidylethanolamine N-methyltransferase (PEMT), are not yet completely understood. The aim of this study was to investigate the roles of the amino acid transporters and these two key enzymes in the uptake of L-[methyl-(11)C]-Met in HCC cells. PROCEDURES: A well-differentiated woodchuck HCC cell line, WCH17, was used for the study. The amino acid transporter of WCH17 cells was assayed to investigate the Met transport process in HCC. WCH17 cells were treated with 5 mM S-adenosylmethionine (SAM) for 8, 16, 24, and 48 h to downregulate MAT2A gene expression. Control or SAM-treated WCH17 cells were pulsed with L-[methyl-(3)H]-Met for 5 min and chased with cold media to mimic the rapid blood clearance of radiolabeled Met (pulse-chase experiment). In parallel, WCH17 cells were transfected with a mouse liver PEMT2 expression vector, and the pulse-chase experiment was performed to investigate the uptake of the radiolabeled Met in HCC cells. The water-soluble, protein, and lipid phases from the total uptake were subsequently extracted and measured, respectively. RESULTS: Met was transported into HCC cells via a facilitative transport process, which was characterized as system L and ASC-like, Na(+) dependent, and low affinity with partial energy dependence. The total uptake of L-[methyl-(3)H]-Met was decreased in HCC cells with SAM treatment. This reduction pattern followed that of MAT2A expression (the duration of SAM treatment). The incorporated (3)H was mostly distributed in the protein phase and, to a lesser degree, in the lipid phase via PE methylation pathway in HCC cells with SAM treatment. The downregulated MAT2A expression led to the decreased uptake in protein and water-soluble phases. In addition, an increased uptake in the lipid phase was observed in WCH17 cells transfected with PEMT2 expression vector. CONCLUSIONS: The amino acid transport processes may be responsible for the rapid accumulation of radiolabeled Met after the intravenous injection of tracers for the imaging of HCC. Upregulated MAT2A expression and impaired PEMT2 activities in HCC are associated with the specific metabolic pattern of L-[methyl-(11)C]-Met detected by PET.

Metabolism of radiolabeled methionine in hepatocellular carcinoma.

PURPOSE: Radiolabeled methionine (Met) promises to be useful in the positron emission tomography (PET) imaging of hepatocellular carcinoma (HCC). However, its metabolic routes in HCC have not yet been fully understood. In this study, the metabolic pathway(s) of radiolabeled Met in HCC were investigated. PROCEDURES: To simulate the rapid blood clearance of radiolabeled Met, pulse-chase experiments were conducted. L-[methyl-(3)H]-Met or L-[1-(14)C]-Met was pulsed over control or cycloheximide-treated WCH17 cells and rat hepatocytes for 5 min and chased with cold media. The water-soluble, lipid-soluble, DNA, RNA, and protein phases were subsequently extracted and measured from the acid-precipitable and acid-soluble fractions of whole cells. The radioactive metabolites Met, S-adenosylmethionine (SAM), S-adenosylhomocysteine, Met sulfoxide, and Met sulfone were further separated by radio thin layer chromatography. RESULTS: (1) The uptake of L-[methyl-(3)H]-Met in both cell types was higher than that of L-[1-(14)C]-Met. In rat hepatocytes, the uptake of L-[methyl-(3)H]-Met was significantly higher than that of L-[1-(14)C]-Met, which may contribute to its physiologic accumulation in surrounding hepatic tissues seen in PET imaging of HCC using L-[methyl-(11)C]-Met. Compared to rat hepatocytes, WCH17 cells had significantly higher uptake of both radiotracers. (2) For L-[methyl-(3)H]-Met, the major intracellular uptake was found mostly in the protein phase and, to a lesser degree, in the phosphatidylethanolamine (PE) methylation pathway, which is fairly stabilized within the 55-min chase period (the main metabolites were SAM, Met, Met sulfoxide, and Met sulfone). In contrast, the uptake of Met in rat hepatocytes mainly points to phosphatidylcholine (PC) synthesis through the PE methylation pathway (the main metabolite was PC). (3) Both cell types incorporated L-[1-(14)C]-Met predominantly into protein synthesis. (4) Finally, when the protein synthesis pathway was inhibited, the incorporation of SAM derived from L-[methyl-(3)H]-Met to lipid class (PC was the main metabolite) occurred at a reduced rate in WCH17 cells, suggesting that the route may be impaired in HCC. CONCLUSIONS: This study demonstrated that different metabolic pathways of radiolabeled Met exist between HCC and surrounding hepatic tissue and contribute to the patterns of increased uptake of radiolabeled Met in HCC.

Effect of the time to intervention on the outcome of thrombosed dialysis access grafts managed percutaneously.

PURPOSE: We aimed to investigate the effect of the time interval from the clinical presentation of a thrombosed dialysis access graft to intervention on procedure success. MATERIALS AND METHODS: Records from two academic institutions for patients who underwent percutaneous thrombectomy of occluded surgical hemodialysis graft access sites in interventional radiology from 2006 to 2011 were reviewed retrospectively. The following data were recorded: gender, age, time and date of the initial request for a thrombectomy and the procedure, age of the surgical access, angiographic outcome, and clinical outcome (successful or unsuccessful postinterventional dialysis). Univariate and multivariate logistic regression were used to evaluate whether the time to intervention significantly affected the study endpoint. RESULTS: In total, 268 percutaneous thrombectomies were performed in 139 patients. Of these 224 (83.5%) were categorized as successful and 44 (16.4%) as unsuccessful. The time to intervention was 19.9±30.1 vs. 22±35 hours for successful and unsuccessful procedures, respectively. The difference between the two was not significant, and there were also no significant differences in covariate distributions between successful and unsuccessful outcomes. CONCLUSION: During the first 72 hours following clinical presentation of a thrombosed dialysis access graft, time to intervention may be considered independent of procedure outcome.

Imaging early stage osteogenic differentiation of mesenchymal stem cells.

Stem cells, such as mesenchymal stem cells (MSCs), contribute to bone fracture repair if they are delivered to the injury site. However, it is difficult to assess the retention and differentiation of these cells after implantation. Current options for non-invasively tracking the transplanted stem cells are limited. Cell-based therapies using MSCs would benefit greatly through the use of an imaging methodology that allows cells to be tracked in vivo and in a timely fashion. In this study, we implemented an in vivo imaging methodology to specifically track early events such as differentiation of implanted human MSCs (hMSCs). This system uses the collagen type 1 (Col1α1) promoter to drive expression of firefly luciferase (luc) in addition to a constitutively active promoter to drive the expression of green fluorescent protein (GFP). The resulting dual-promoter reporter gene system provides the opportunity for osteogenic differentiation-specific luc expression for in vivo imaging and constitutive expression of GFP for cell sorting. The function of this dual-promoter reporter gene was validated both in vitro and in vivo. In addition, the ability of this dual-promoter reporter system to image an early event of osteogenic differentiation of hMSCs was demonstrated in a murine segmental bone defect model in which reporter-labeled hMSCs were seeded into an alginate hydrogel scaffold and implanted directly into the defect. Bioluminescence imaging (BLI) was performed to visualize the turn-on of Col1α1 upon osteogenic differentiation and followed by X-ray imaging to assess the healing process for correlation with histological analyses.

Percutaneous CT-guided cryoablation of the dorsal penile nerve for treatment of symptomatic premature ejaculation.

PURPOSE: To evaluate expansion of image-guided interventional cryoablation techniques usually employed for pain management to address the feasibility, safety, and efficacy of treatment for a urologic condition with otherwise limited treatment options, premature ejaculation (PE). MATERIALS AND METHODS: Prospective institutional review board approval was obtained, and 24 subjects with PE were enrolled. All patients underwent unilateral percutaneous computed tomography-guided cryoablation of the dorsal penile nerve (DPN). Postprocedural intravaginal ejaculatory latency times (IELTs) and PE Profile (PEP) results served as outcome variables. In addition, subjects were asked whether they would have the procedure done again based on their experience at the 180- and 360-day marks. RESULTS: The technical success rate was 100%. Baseline average IELT was 54.7 seconds ± 7.8 (n = 24), which increased to a maximum of 256 seconds ± 104 (n = 11; P = .241) by day 7 and decreased to 182.5 seconds ± 87.8 (n = 6; P = .0342) by day 90. The mean IELT remained at 182.5 seconds ± 27.6 at day 180 (n = 23; P<.0001) and decreased to 140.9 seconds ± 83.6 by 1 year (n = 22; P<.001). PEP scores improved overall, IELTs significantly improved at 180 and 360 days, and 83% of subjects reported that they would undergo the procedure again if given the same opportunity. There were no procedure-related complications. CONCLUSIONS: CT-guided percutaneous unilateral cryoablation of the DPN is a feasible, safe, single-day outpatient procedure for the treatment of symptomatic PE.

Murine leukemia virus envelope gp70 is a shared biomarker for the high-sensitivity quantification of murine tumor burden.

The preclinical development of anticancer drugs including immunotherapeutics and targeted agents relies on the ability to detect minimal residual tumor burden as a measure of therapeutic efficacy. Real-time quantitative (qPCR) represents an exquisitely sensitive method to perform such an assessment. However, qPCR-based applications are limited by the availability of a genetic defect associated with each tumor model under investigation. Here, we describe an off-the-shelf qPCR-based approach to detect a broad array of commonly used preclinical murine tumor models. In particular, we report that the mRNA coding for the envelope glycoprotein 70 (gp70) encoded by the endogenous murine leukemia virus (MuLV) is universally expressed in 22 murine cancer cell lines of disparate histological origin but is silent in 20 out of 22 normal mouse tissues. Further, we detected the presence of as few as 100 tumor cells in whole lung extracts using qPCR specific for gp70, supporting the notion that this detection approach has a higher sensitivity as compared with traditional tissue histology methods. Although gp70 is expressed in a wide variety of tumor cell lines, it was absent in inflamed tissues, non-transformed cell lines, or pre-cancerous lesions. Having a high-sensitivity biomarker for the detection of a wide range of murine tumor cells that does not require additional genetic manipulations or the knowledge of specific genetic alterations present in a given neoplasm represents a unique experimental tool for investigating metastasis, assessing antitumor therapeutic interventions, and further determining tumor recurrence or minimal residual disease.

The effect of fasting on PET Imaging of Hepatocellular Carcinoma.

The clinical utility of positron emission tomography (PET) imaging for liver cancer applications is not clearly defined either for diagnosis or treatment assessment. Previous clinical studies demonstrated that fluorodeoxyglucose (FDG) did not show uptake in some hepatocellular carcinoma (HCC) while acetate showed uptake. Pre-imaging fasting is required for clinical PET imaging with FDG. No studies were done to confirm the effect of fasting on acetate uptake in HCC for PET imaging. We investigated this situation with a woodchuck model of viral infection-induced HCC. METHODS: Four tumor-bearing and one control woodchucks were involved in this study. They were first imaged by PET in fed state followed by another imaging session one week later when they were fasted over-night. Some animals also had FDG-PET scan that was acquired later on the same day. After imaging studies, animals were sacrificed, and their liver excised for histology. Standardized Uptake Value (SUV) was calculated using a region of interest (ROI) placed on each tumor with focal uptake. RESULTS: Acetate showed uptake in each HCC lesion when the animals were either fasted or fed with no significant difference in SUV values (p=0.177); some of the tumors were histologically confirmed as well-differentiated HCC while others were confirmed as moderately- or poorly-differentiated HCC; no focal uptake was found in the control animal. For the accompanying FDG scans, the uptake was detected only in animals that were fasted although the uptake pattern was different from that with acetate. CONCLUSION: This study provided a hint that fasting or not has little impact on PET imaging of HCC with acetate. It also confirmed prior finding regarding tumor heterogeneity that led to different tracer uptake pattern in the same tumor. Human studies are needed to validate the findings from this pre-clinical investigation.

Radio-deoxynucleoside Analogs used for Imaging tk Expression in a Transgenic Mouse Model of Induced Hepatocellular Carcinoma.

PURPOSE: A group of radiolabeled thymidine analogs were developed as radio-tracers for imaging herpes viral thymidine kinase (HSV1-tk) or its variants used as reporter gene. A transgenic mouse model was created to express tk upon liver injury or naturally occurring hepatocellular carcinoma (HCC). The purpose of this study was to use this unique animal model for initial testing with radio-labeled thymidine analogs, mainly a pair of newly emerging nucleoside analogs, D-FMAU and L-FMAU. METHODS: A transgeneic mouse model was created by putting a fused reporter gene system, firefly luciferase (luc) and HSV1-tk, under the control of mouse alpha fetoprotein (Afp) promoter. Initial multimodal imaging, which was consisted of bioluminescent imaging (BLI) and planar gamma scintigraphy with [(125)I]-FIAU, was used for examining the model creation in the new born and liver injury in the adult mice. Carcinogen diethylnitrosamine (DEN) was then administrated to induce HCC in these knock-in mice such that microPET imaging could be used to track the activity of Afp promoter during tumor development and progression by imaging tk expression first with [(18)F]-FHBG. Dynamic PET scans with D-[(18)F]-FMAU and L-[(18)F]-FMAU were then performed to evaluate this pair of relatively new tracers. Cells were derived from these liver tumors for uptake assays using H-3 labeled version of PET tracers. RESULTS: The mouse model with dual reporters: HSV1-tk and luc placed under the transcriptional control of an endogenous Afp promoter was used for imaging studies. The expression of the Afp gene was highly specific in proliferative hepatocytes, in regenerative liver, and in developing fetal liver, and thus provided an excellent indicator for liver injury and cancer development in adult mice. Both D-FMAU and L-FMAU showed stable liver tumor uptake where the tk gene was expressed under the Afp promoter. The performance of this pair of tracers was slightly different in terms of signal-to-background ratio as well as tracer clearance. CONCLUSION: The newly created knock-in mouse model was used to demonstrate the use of the dual-reporter genes driven by well-characterized cancer-specific transcriptional units in conjunction with in vivo imaging as a paradigm in studying naturally occurring cancer in live animals. While BLI is suitable for small animal imaging with luc expression, PET with L-FMAU seemed be the choice for liver injury or liver cancer imaging with this animal model for future investigations.

Percutaneous image-guided delivery for the transplantation of mesenchymal stem cells in the setting of degenerated intervertebral discs.

PURPOSE: The delivery of mesenchymal stem cells (MSCs) to their site of action has remained a technical hurdle for clinical researchers in the expanding field of stem cell-based therapy. The purpose of this study was to test the feasibility of percutaneous image-guided needle delivery of bone marrow-derived human MSCs (hMSCs) to degenerated intervertebral discs (IVDs) in a preclinical model and to assess the containment of these cells within the IVDs. MATERIALS AND METHODS: Degeneration was induced in the lumbar IVDs of four 28-35-kg female pigs. Approximately 100,000 iodine-124 2'-fluoro-2'-deoxy-1ß-D-arabinofuranosyl-5-iodouracil-labeled hMSCs were delivered under fluoroscopic guidance to one of the affected discs in each of the animals. The remaining levels served as internal controls. The animals were imaged by computed tomography (CT) and positron emission tomography (PET) immediately after delivery and 3 days after the procedure. Fifteen days after transplantation, immunohistochemical staining was performed on harvested discs to confirm the presence of delivered hMSCs. RESULTS: After refinement of the technique, PET-CT images on the day of cell transplantation showed initial deposition of the delivered radiolabeled MSCs to the IVD. An additional PET-CT study obtained 3 days later confirmed persistence and containment of activity in the IVD. Findings of histologic evaluation for the presence of human Alu sequences were positive in the treated discs and negative in the controls. CONCLUSIONS: Image-guided needle delivery of MSCs for treatment of degenerated IVDs is feasible as demonstrated in this preclinical model. Trials of this minimally invasive technique in humans are warranted.

PET imaging of hepatocellular carcinoma with 18F-fluoroethylcholine and 11C-choline.

PURPOSE: Choline-based radiotracers have been studied for PET imaging of hepatocellular carcinoma (HCC). Using an (18)F-labeled choline analog, instead of the (11)C-labeled native choline, would facilitate its widespread use in the clinic. In this study, PET with (18)F-fluoroethylcholine (FEC) and (11)C-choline (CHOL) were compared using an animal model of HCC. The effects of fasting on the performance of choline-based tracers were also investigated. METHODS: A woodchuck model of HCC was used to compare the two tracers, which were administered and imaged in sequence during the same imaging session. Dynamic PET images were generated spanning 50 min starting from tracer injection. Time-activity curves and tracer contrast were calculated in liver regions with tracer accumulation, and the contrast at a late time-point with the two tracers, and between fasted and nonfasted states, were compared. RESULTS: Foci of HCC with increased uptake ranged in size from 1.0 to 1.6 cm, with mean tumor-to-background contrast of 1.3 with FEC and 1.5 with CHOL at 50 min after injection. The tracers show similar patterns of uptake immediately following administration, and both activities plateaued at 10 min after injection. No significant differences in uptake dynamics or final contrast were observed between the fasted and nonfasted states. CONCLUSION: PET imaging of HCC is possible with both CHOL and FEC. Fasting was not found to affect accumulation of either tracer. These results encourage further investigation into the clinical utility of FEC for HCC imaging.

[(Methyl)1-(11)c]-acetate metabolism in hepatocellular carcinoma.

PURPOSE: Studies have established the value of [(methyl)1-(11)C]-acetate ([(11)C]Act) combined with 2-deoxy-2[(18)F]fluoro-D-glucose (FDG) for detecting hepatocellular carcinoma (HCC) using positron emission tomography (PET). In this study, the metabolic fate of [(11)C]Act in HCC was characterized. METHODS: Experiments with acetic acid [1-(14)C] sodium salt ([(14)C]Act) were carried out on WCH-17 cells and freshly derived rat hepatocytes. PET scans with [(11)C]Act were also carried out on woodchucks with HCC before injection of [(14)C]Act. The radioactivity levels in different metabolites were quantified with thin-layer chromatography. RESULTS: In WCH-17 cells, the predominant metabolite was phosphatidylcholine (PC). Regions of HCCs with the highest [(11)C]Act uptake had higher radioactivity accumulation in lipid-soluble compounds than surrounding hepatic tissues. In those regions, PC and triacylglycerol (TG) accumulated more radioactivity than in surrounding hepatic tissues. CONCLUSIONS: High [(11)C]Act uptake in HCC is associated with increased de novo lipogenesis. PC and TG are the main metabolites into which the radioactive label from [(11)C]Act is incorporated in HCC.

Imaging lipid synthesis in hepatocellular carcinoma with [methyl-11c]choline: correlation with in vivo metabolic studies.

UNLABELLED: PET with [methyl-(11)C]-choline (11C-choline) can be useful for detecting well-differentiated hepatocellular carcinoma (HCC) that is not 18F-FDG-avid. This study was designed to examine the relationship between choline metabolism and choline tracer uptake in HCC for PET with 11C-choline. METHODS: Dynamic PET scans of 11C-choline were acquired using the woodchuck models of HCC. After imaging, [methyl-(14)C]-choline was injected, and metabolites from both HCC tissue samples and the surrounding hepatic tissues were extracted and analyzed by radio-high-performance liquid chromatography. The enzymatic activities of choline kinase and choline-phosphate cytidylyltransferase were assayed for correlation with the imaging and metabolism data. RESULTS: PET with 11C-choline showed an HCC detection rate of 9 of 10. The tumor-to-liver ratio for the 9 detected HCCs was 1.89±0.55. Hematoxylin-eosin staining confirmed that all spots with high tracer uptake were well-differentiated HCCs. Variation of radioactivity distribution within HCCs indicated a heterogeneous uptake of choline. The activities of both choline kinase and choline-phosphate cytidylyltransferase were found to be significantly higher in HCC than in the surrounding hepatic tissues. The major metabolites of 11C-choline were phosphocholine in HCC and betaine and choline in the surrounding hepatic tissues at 12 min after injection; in HCC, phosphocholine rapidly converted to phosphatidylcholine at 30 min after injection. CONCLUSION: HCCs display enhanced uptake of radiolabeled choline despite a moderate degree of physiologic uptake in the surrounding hepatic tissues. Initially, increased radiolabeled choline uptake in HCCs is associated with the transport and phosphorylation of choline; as time passes, the increased uptake of radiolabeled choline reflects increased phosphatidylcholine synthesis derived from radiolabeled cytidine 5'-diphosphocholine (CDP-choline) in HCCs. In contrast, the surrounding hepatic tissues exhibit extensive oxidation of radiolabeled choline via the phosphatidylethanolamine methylation pathway, a major contributor to the observed physiologic uptake.

Transport and metabolism of radiolabeled choline in hepatocellular carcinoma.

Altered choline (Cho) metabolism in cancerous cells can be used as a basis for molecular imaging with PET using radiolabeled Cho. In this study, the metabolism of tracer Cho was investigated in a woodchuck hepatocellular carcinoma (HCC) cell line (WCH17) and in freshly derived rat hepatocytes. The transporter responsible for [(11)C]-Cho uptake in HCC was also characterized in WCH17 cells. The study helped to define the specific mechanisms responsible for radio-Cho uptake seen on the PET images of primary liver cancer such as HCC. Cells were pulsed with [(14)C]-Cho for 5 min and chased for varying durations in cold media to simulate the rapid circulation and clearance of [(11)C]-Cho. Radioactive metabolites were extracted and analyzed by radio-HPLC and radio-TLC. The Cho transporter (ChoT) was characterized in WCH17 cells. WCH17 cells showed higher (14)C uptake than rat primary hepatocytes. [(14)C]-Phosphocholine (PC) was the major metabolite in WCH17. In contrast, the intracellular Cho in primary hepatocytes was found to be oxidized to betaine (partially released into media) and, to a lesser degree, phosphorylated to PC. [(14)C]-Cho uptake by WCH17 cells was found to have both facilitative transport and nonfacilitative diffusion components. The facilitative transport was characterized by Na(+) dependence and low affinity (K(m) = 28.59 ± 6.75 µM) with partial energy dependence. In contrast, ChoT in primary hepatocytes is Na(+) independent and low affinity. Our data suggest that transport and phosphorylation of Cho are responsible for the tracer accumulation during [(11)C]-Cho PET imaging of HCC. WCH17 cells incorporate [(14)C]-Cho preferentially into PC. Conversion of [(14)C]-PC into phosphatidylcholine occurred slowly in vitro. Basal oxidation and phosphorylation activities in surrounding hepatic tissue contribute to the background seen in [(11)C]-Cho PET images.