Intrabiliary RF heat-enhanced local chemotherapy of a cholangiocarcinoma cell line: monitoring with dual-modality imaging--preclinical study.

PURPOSE: To determine whether magnetic resonance (MR) imaging heating guidewire-mediated radiofrequency (RF) hyperthermia could enhance the therapeutic effect of gemcitabine and 5-fluorouracil (5-FU) in a cholangiocarcinoma cell line and local deposit doses of chemotherapeutic drugs in swine common bile duct (CBD) walls. MATERIALS AND METHODS: The animal protocol was approved by the institutional animal care and use committee. Green fluorescent protein-labeled human cholangiocarcinoma cells and cholangiocarcinomas in 24 mice were treated with (a) combination therapy with chemotherapy (gemcitabine and 5-FU) plus RF hyperthermia, (b) chemotherapy only, (c) RF hyperthermia only, or (d) phosphate-buffered saline. Cell proliferation was quantified, and tumor changes over time were monitored with 14.0-T MR imaging and optical imaging. To enable further validation of technical feasibility, intrabiliary local delivery of gemcitabine and 5-FU was performed by using a microporous balloon with (eight pigs) or without (eight pigs) RF hyperthermia. Chemotherapy deposit doses in the bile duct walls were quantified by means of high-pressure liquid chromatography. The nonparametric Mann-Whitney U test and the paired-sample Wilcoxon signed rank test were used for data analysis. RESULTS: Combination therapy induced lower mean levels of cell proliferation than chemotherapy only and RF hyperthermia only (0.39 ± 0.13 [standard deviation] vs 0.87 ± 0.10 and 1.03 ± 0.13, P < .001). Combination therapy resulted in smaller relative tumor volume than chemotherapy only and RF hyperthermia only (0.65 ± 0.03 vs 1.30 ± 0.021 and 1.37 ± 0.05, P = .001). Only in the combination therapy group did both MR imaging and optical imaging show substantial decreases in apparent diffusion coefficients and fluorescent signals in tumor masses immediately after the treatments. Chemotherapy quantification showed a higher average drug deposit dose in swine CBD walls with intrabiliary RF hyperthermia than without it (gemcitabine: 0.32 mg/g of tissue ± 0.033 vs 0.260 mg/g ± 0.030 and 5-FU: 0.660 mg/g ± 0.060 vs 0.52 mg/g ± 0.050, P < .05). CONCLUSION: The use of intrabiliary MR imaging heating guidewire-mediated RF hyperthermia can enhance the chemotherapeutic effect on a human cholangiocarcinoma cell line and local drug deposition in swine CBD tissues.

Diffusion-weighted MRI monitoring of pancreatic cancer response to radiofrequency heat-enhanced intratumor chemotherapy.

The aim of this study was to evaluate the feasibility of using diffusion-weighted MRI to monitor the early response of pancreatic cancers to radiofrequency heat (RFH)-enhanced chemotherapy. Human pancreatic carcinoma cells (PANC-1) in different groups and 24 mice with pancreatic cancer xenografts in four groups were treated with phosphate-buffered saline (PBS) as a control, RFH at 42 °C, gemcitabine and gemcitabine plus RFH at 42 °C. One day before and 1, 7 and 14 days after treatment, diffusion-weighted MRI and T2 -weighted imaging were applied to monitor the apparent diffusion coefficients (ADCs) of tumors and tumor growth. MRI findings were correlated with the results of tumor apoptosis analysis. In the in vitro experiments, the quantitative viability assay showed lower relative cell viabilities for treatment with gemcitabine plus RFH at 42 °C relative to treatment with RFH only and gemcitabine only (37 ± 5% versus 65 ± 4% and 58 ± 8%, respectively, p < 0.05). In the in vivo experiments, the combination therapy resulted in smaller relative tumor volumes than RFH only and chemotherapy only (0.82 ± 0.17 versus 2.23 ± 0.90 and 1.64 ± 0.44, respectively, p = 0.003). In vivo, 14-T MRI demonstrated a remarkable decrease in ADCs at day 1 and increased ADCs at days 7 and 14 in the combination therapy group. The apoptosis index in the combination therapy group was significantly higher than those in the chemotherapy-only, RFH-only and PBS treatment groups (37 ± 6% versus 20 ± 5%, 8 ± 2% and 3 ± 1%, respectively, p < 0.05). This study confirms that it is feasible to use MRI to monitor RFH-enhanced chemotherapy in pancreatic cancers, which may present new options for the efficient treatment of pancreatic malignancies using MRI/RFH-integrated local chemotherapy.

MRI-monitored intra-shunt local agent delivery of motexafin gadolinium: towards improving long-term patency of TIPS.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) has become an important and effective interventional procedure in treatment of the complications related to portal hypertension. Although the primary patency of TIPS has been greatly improved due to the clinical application of cover stent-grafts, the long-term patency is still suboptimal. This study was to investigate the feasibility of using magnetic resonance imaging (MRI)-monitored intra-shunt local agent delivery of motexafin gadolinium (MGd) into shunt-vein walls of TIPS. This new technique aimed to ultimately inhibit shuntstenosis of TIPS. METHODOLOGY: Human umbilical vein smooth muscle cells (SMCs) were incubated with various concentrations of MGd, and then examed by confocal microscopy and T1-map MRI. In addition, the proliferation of MGd-treated cells was evaluated. For in vivo validation, seventeen pigs underwent TIPS. Before placement of the stent, an MGd/trypan-blue mixture was locally delivered, via a microporous balloon, into eleven shunt-hepatic vein walls under dynamic MRI monitoring, while trypan-blue only was locally delivered into six shunt-hepatic vein walls as serve as controls. T1-weighted MRI of the shunt-vein walls was achieved before- and at different time points after agent injections. Contrast-to-noise ratio (CNR) of the shunt-vein wall at each time-point was measured. Shunts were harvested for subsequent histology confirmation. PRINCIPAL FINDINGS: In vitro studies confirmed the capability of SMCs in uptaking MGds in a concentration-dependent fashion, and demonstrated the suppression of cell proliferation by MGds as well. Dynamic MRI displayed MGd/blue penetration into the shunt-vein walls, showing significantly higher CNR of shunt-vein walls on post-delivery images than on pre-delivery images (49.5±9.4 vs 11.2±1.6, P<0.01), which was confirmed by histology. CONCLUSION: Results of this study indicate that MRI-monitored intra-shunt local MGd delivery is feasible and MGd functions as a potential therapeutic agent to inhibit the proliferation of SMCs, which may open alternative avenues to improve the long-term patency of TIPS.

3.0-T MR imaging of intracoronary local delivery of motexafin gadolinium into coronary artery walls.

PURPOSE: To develop a technique with clinical 3.0-T magnetic resonance (MR) imaging to delineate local contrast agent distribution in coronary artery walls for potential molecular MR imaging-guided local gene or drug therapy of atherosclerotic coronary artery disease. MATERIALS AND METHODS: This animal protocol was approved by the institutional animal care and use committee and was in compliance with the Guide for the Care and Use of Laboratory Animals. For in vitro confirmation, human arterial smooth muscle cells (SMCs) were used to determine capability of SMCs in uptake of motexafin gadolinium (MGd) and its optimal dose. For ex vivo evaluation, a 2-mL mixture of MGd and trypan blue was locally infused into coronary artery walls of six cadaveric pig hearts with MR monitoring and an MR imaging guidewire, surface coils, or both. For in vivo validation, the balloon catheter was placed into coronary arteries of seven living pigs, and the MGd and trypan blue mixture was infused into arterial walls with MR guidance. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of coronary artery walls were recorded by using different coils between pre- and postcontrast infusion, with subsequent histologic confirmation. Paired Student t tests were used to compare average SNRs and CNRs of arterial walls before and after contrast agent infusion with different coils. RESULTS: SMCs could take up MGd with the optimal concentration at 150 µmol/L. Average SNR with the MR imaging guidewire and surface coil combination was significantly higher than that with the MR imaging guidewire only or with surface coils only (P < .05), and average SNR and CNR of postinfusion MR imaging was significantly higher than that of preinfusion MR imaging (P < .05). Histologic analysis was used to confirm successful intracoronary infiltration of MGd and trypan blue within coronary artery walls. CONCLUSION: MR imaging can be used to delineate locally infused contrast agent distribution in coronary artery walls. This establishes groundwork for development of molecular MR imaging-guided intracoronary therapy.

Long-term outcomes after percutaneous patent foramen ovale closure.

Percutaneous patent foramen ovale (PFO) closure is a treatment for cryptogenic stroke and migraine headache. The goal of this study was to assess long-term outcomes of patients treated with percutaneous PFO closure. Records of patients with percutaneous PFO closure at Emory University Hospital from February 2002 to July 2009 were reviewed. Follow-up telephone questionnaire and chart review assessed recurrent stroke, migraine, and complications. Data was reviewed on 414 consecutive patients. Long-term follow-up was obtained in 207 of patients, and mean follow up was 4.6 ± 2.0 years. Cryptogenic stroke was the primary indication for intervention in 193 (93%) patients. Thirteen (7%) patients had a recurrent neurologic event post closure. In patients with multiple neurological events at baseline, 17% (n = 11) had a recurrent event, compared with 2% (n = 2) of patients with a single neurological event prior to PFO-closure (P < 0.002). Post closure, migraine frequency and severity declined from 4.5 to 1.1 migraine/month (P < 0.01) and 7.2 to 3.6 out of 10 (P < 0.01) in patients with history of migraine (n = 60). Thirty-day mortality was 1% (n = 2). One patient had device erosion 5 years post-procedure requiring emergent surgery. Atrial fibrillation was newly diagnosed in 8 (4%) patients within 6 months. In conclusion, the long-term rate of recurrent stroke after PFO closure is low in patients with a single neurological event at baseline. Serious long-term complications after PFO closure are rare. PFO closure may decrease the frequency and severity of migraine.

Repair of prosthetic mitral valve paravalvular leak using an off-pump transapical approach.

Patients who present with significant paravalvular regurgitation after mitral valve replacement remain a difficult patient population and high-risk surgical candidates. We present 3 cases of transapical closure of mitral valve paravalvular leak (PVL) after mitral valve replacement using Amplatzer closure devices (AGA Medical Corp, Plymouth, MN). All 3 patients experienced decreased regurgitation at the site of the closure as well as symptomatic improvement in their heart failure.

Development of an intrabiliary MR imaging-monitored local agent delivery technique: a feasibility study in pigs.

PURPOSE: To investigate the feasibility of using magnetic resonance (MR) imaging to monitor intrabiliary delivery of motexafin gadolinium (MGd) into pig common bile duct (CBD) walls. MATERIALS AND METHODS: Animal studies were approved by the Institutional Animal Care and Use Committee. Initially, human cholangiocarcinoma cells were treated with various concentrations of MGd, a compound serving as a T1-weighted MR imaging contrast agent, chemotherapy drug, and cell marker. These cells were then examined by means of confocal microscopy to confirm the intracellular uptake of MGd. In addition, an MGd/trypan blue mixture was locally infused into CBD walls of six cadaveric pigs using a microporous balloon catheter. CBDs of six pigs were infused with saline to serve as controls. Ex vivo T1-weighted MR imaging of these CBDs was performed. For in vivo technical validation, the microporous balloon catheter was placed in the CBD by means of a transcholecytic access to deliver MGd/trypan blue into CBD walls of six living pigs. T1-weighted images were obtained with both a surface coil and an intrabiliary MR imaging guidewire, and contrast-to-noise ratios of CBD walls before and after MGd/trypan blue infusions were compared in the two groups by means of paired t test, with subsequent histologic analysis to confirm the penetration and distribution of the MGd/trypan blue agent into CBD walls. RESULTS: In vitro experiments confirmed uptake of MGd by human cholangiocarcinoma cells. The ex vivo experiments demonstrated the penetration of MGd/trypan blue into the CBD walls. The in vivo experiment confirmed the uptake of MGd/trypan blue, showing an increased contrast-to-noise ratio for the CBD after administration of the mixture, compared with images obtained prior to MGd/trypan blue administration (11.6 ± 4.2 [standard deviation] vs 5.7 ± 2.8; P = .04). Histologic results depicted the blue dye stains and red fluorescence of MGd in CBD walls, confirming the imaging findings. CONCLUSION: It is feasible to use MR imaging to monitor the penetration of locally delivered MGd into pig CBD walls.

Ventricular noncompaction and associated cardiac anomalies.

An 80-year-old woman was referred for transcatheter aortic valve implantation for correction of aortic stenosis. An echocardiogram at the author's institution revealed severe hypertrophy of the left ventricle with deep recesses into the myocardium and hypokinesis involving the left ventricular apex. In addition, there was subaortic stenosis secondary to a muscular ridge. The aortic valve was only mildly stenotic. In this Cardiology Grand Rounds, the authors present a rare case of ventricular noncompaction and review the literature on this subject and its association with other cardiac abnormalities.

A right atrial mass, patent foramen ovale, and indwelling central venous catheter in a patient with a malignancy: a diagnostic and therapeutic dilemma.

A 33-year-old woman with a history of gestational trophoblastic disease presented for investigation of a right atrial mass. She had been receiving chemotherapy administered via a Port-a-Cath system for 2 months prior to presentation. On transesophageal echocardiography and magnetic resonance imaging, she was found to have a mass attached to the right atrial free wall, with a segment projecting across a patent foramen ovale. Because of the risk for an embolic event, the mass was surgically removed and the patent foramen ovale repaired. Pathology showed an organized thrombus. This case emphasizes the need for high suspicion for thrombus when a right atrial mass is found in a patient with a hypercoagulable state due to underlying malignancy who has a central venous catheter.

Anemia, hemorrhage, and transfusion in percutaneous coronary intervention, acute coronary syndromes, and ST-segment elevation myocardial infarction.

Advances in antithrombotic and antiplatelet therapies have led to a reduction in ischemic event rates in percutaneous coronary intervention (PCI), acute coronary syndromes (ACS), and ST-segment elevation myocardial infarction (STEMI) but have generally resulted in an increased risk of hemorrhagic complications. In these settings, both baseline anemia and acute hemorrhage occur with relative frequency and are associated with increased morbidity and mortality. Although commonly treated with blood transfusion, this intervention may accentuate rather than attenuate both short-term and long-term risk. This review discusses the pathophysiology of anemia and the impact of anemia and transfusion on morbidity and mortality in PCI, ACS, and STEMI.