Jung-Kyu Han

Biodegradable-polymer drug-eluting stents vs. bare metal stents vs. durable-polymer drug-eluting stents: a systematic review and Bayesian approach network meta-analysis

BACKGROUND The aim of this study was to compare the safety and efficacy of biodegradable-polymer (BP) drug-eluting stents (DES), bare metal stents (BMS), and durable-polymer DES in patients undergoing coronary revascularization, we performed a systematic review and network meta-analysis using a Bayesian framework. METHODS AND RESULTS Study stents included BMS, paclitaxel-eluting (PES), sirolimus-eluting (SES), endeavor zotarolimus-eluting (ZES-E), cobalt-chromium everolimus-eluting (CoCr-EES), platinium-chromium everolimus-eluting (PtCr-EES), resolute zotarolimus-eluting (ZES-R), and BP biolimus-eluting stents (BP-BES). After a systematic electronic search, 113 trials with 90 584 patients were selected. The principal endpoint was definite or probable stent thrombosis (ST) defined according to the Academic Research Consortium within 1 year. RESULTS Biodegradable polymer-biolimus-eluting stents [OR, 0.56; 95% credible interval (CrI), 0.33-0.90], SES (OR, 0.53; 95% CrI, 0.38-0.73), CoCr-EES (OR, 0.34; 95% CrI, 0.23-0.52), and PtCr-EES (OR, 0.31; 95% CrI, 0.10-0.90) were all superior to BMS in terms of definite or probable ST within 1 year. Cobalt-chromium everolimus-eluting stents demonstrated the lowest risk of ST of all stents at all times after stent implantation. Biodegradable polymer-biolimus-eluting stents was associated with a higher risk of definite or probable ST than CoCr-EES (OR, 1.72; 95% CrI, 1.04-2.98). All DES reduced the need for repeat revascularization, and all but PES reduced the risk of myocardial infarction compared with BMS. CONCLUSIONS All DESs but PES and ZES-E were superior to BMS in terms of ST within 1 year. Cobalt-chromium everolimus-eluting stents was safer than any DES even including BP-BES. Our results suggest that not only the biodegradability of polymer, but the optimal combination of stent alloy, design, strut thickness, polymer, and drug all combined determine the safety of DES.

Peroxisome Proliferator-Activated Receptor-δ Agonist Enhances Vasculogenesis by Regulating Endothelial Progenitor Cells Through Genomic and Nongenomic Activations of the Phosphatidylinositol 3-Kinase/Akt Pathway

Background— Despite the therapeutic potential of endothelial progenitor cells (EPCs) in ischemic vascular diseases, their insufficient numbers limit clinical applications. Peroxisome proliferator–activated receptor (PPAR)-&dgr; belongs to the nuclear hormone receptor superfamily, and its functions in various tissues and cells are almost unexplored, especially with respect to vascular biology. Methods and Results— PPAR-&dgr; activation in EPCs phosphorylated Akt, and this phosphorylation was mediated not only by genomic but also by nongenomic pathways through interaction with the regulatory subunit of phosphatidylinositol 3-kinase. PPAR-&dgr; activation with agonist (GW501516 or L-165041) increased the proliferation of human EPCs and protected them from hypoxia-induced apoptosis. In addition, PPAR-&dgr; activation enhanced EPC functions, such as transendothelial migration, and tube formation. These actions by PPAR-&dgr; activation in EPCs were dependent on the phosphatidylinositol 3-kinase/Akt pathway. In ischemic hindlimb of mice models, transplantation of PPAR-&dgr; agonist–treated human or mouse EPCs enhanced blood flow recovery to ischemic limbs compared with vehicle-treated EPCs. In EPCs from PPAR-&dgr;–knockout mice, however, treatment with PPAR-&dgr; agonist did not enhance in vivo vasculogenic potential. Systemic administration of PPAR-&dgr; agonist increased hematopoietic stem cells in bone marrow and EPCs in peripheral blood, leading to improved vasculogenesis with incorporation of bone marrow–derived cells to new vessels in a corneal neovascularization model and limb salvage with better blood flow in an ischemic hindlimb model. Conclusions— The results of our study suggest that PPAR-&dgr; agonist has therapeutic vasculogenic potential for the treatment of ischemic cardiovascular diseases.

Wnt Signaling Exerts an Antiproliferative Effect on Adult Cardiac Progenitor Cells Through IGFBP3

Rationale: Recent work in animal models and humans has demonstrated the presence of organ-specific progenitor cells required for the regenerative capacity of the adult heart. In response to tissue injury, progenitor cells differentiate into specialized cells, while their numbers are maintained through mechanisms of self-renewal. The molecular cues that dictate the self-renewal of adult progenitor cells in the heart, however, remain unclear. Objective: We investigate the role of canonical Wnt signaling on adult cardiac side population (CSP) cells under physiological and disease conditions. Methods and Results: CSP cells isolated from C57BL/6J mice were used to study the effects of canonical Wnt signaling on their proliferative capacity. The proliferative capacity of CSP cells was also tested after injection of recombinant Wnt3a protein (r-Wnt3a) in the left ventricular free wall. Wnt signaling was found to decrease the proliferation of adult CSP cells, both in vitro and in vivo, through suppression of cell cycle progression. Wnt stimulation exerted its antiproliferative effects through a previously unappreciated activation of insulin-like growth factor binding protein 3 (IGFBP3), which requires intact IGF binding site for its action. Moreover, injection of r-Wnt3a after myocardial infarction in mice showed that Wnt signaling limits CSP cell renewal, blocks endogenous cardiac regeneration and impairs cardiac performance, highlighting the importance of progenitor cells in maintaining tissue function after injury. Conclusions: Our study identifies canonical Wnt signaling and the novel downstream mediator, IGFBP3, as key regulators of adult cardiac progenitor self-renewal in physiological and pathological states.

Comparison Among Drug-Eluting Balloon, Drug-Eluting Stent, and Plain Balloon Angioplasty for the Treatment of In-Stent Restenosis : A Network Meta-Analysis of 11 Randomized, Controlled Trials

OBJECTIVES A Bayesian network meta-analysis was performed comparing the efficacy and safety of drug-eluting balloons (DEB), drug-eluting stents (DES), or plain old balloon angioplasty (POBA) for treatment of in-stent restenosis (ISR). BACKGROUND Optimal treatment options for ISR have not been well established. METHODS Randomized, controlled trials comparing DEB, DES, and POBA for the treatment of ISR after percutaneous coronary intervention with bare metal stent or DES were included. The primary outcome was target lesion revascularization (TLR). The pairwise posterior median odds ratio (OR) with 95% credible interval (CrI) was the effect measure. RESULTS This analysis included 2,059 patients from 11 RCTs. The risk of TLR was markedly lower in patients treated with DEB (OR: 0.22, 95% CrI: 0.10 to 0.42) or DES (OR: 0.24, 95% CrI: 0.11 to 0.47) than in those treated with POBA in a random-effects model. In a comparison of DEB and DES, the risk of TLR (OR: 0.92, 95% CrI: 0.43 to 1.90) was similar. The risk of MI or all-cause mortality was lowest in the DEB group compared with the DES and POBA groups, which did not meet statistical significance. The risk of major adverse cardiac events, which was mainly driven by TLR, was also significantly lower in the DEB or and DES group (OR: 0.28, 95% CrI: 0.14 to 0.53) than in the POBA group, but it was similar between the DEB and DES groups (OR: 0.84, 95% CrI: 0.45 to 1.50). The probability of being ranked as the best treatment was 59.9% (DEB), 40.1% (DES), and 0.1% (POBA) in terms of TLR, whereas it was 63.0% (DEB), 35.3% (POBA), and 1.7% (DES) in terms of MI. CONCLUSIONS Local drug delivery by DEB or DES for ISR lesions was markedly better than POBA in preventing TLR, but not for MI or mortality. Among the 2 different strategies of drug delivery for ISR lesions, treatment with DEB showed a trend of less development of MI than did treatment with DES.

Dysplastic nodules of the liver: imaging findings

AbstractBackground: To verify characteristic features of hepatic dysplastic nodules at different imaging modalities. Methods: Twenty-eight patients with 37 dysplastic nodules of the liver (0.8–3.0 cm) underwent sonography (28 patients), computed tomography (CT; 24 patients), magnetic resonance (MR; 11 patients), and angiography (12 patients). Each nodule was analyzed for echogenicity, attenuation, signal intensity, and vascularity. Results: Echogenicity of nodules was high in 16 (43%), homogeneous in two (6%), and low in 19 (51%) of 37 nodules. Attenuation of nodules was high in one (7%), homogeneous in four (26%), and low in 10 (67%) of 15 nodules on the arterial-phase CT images; homogeneous in five (33%) and low in 10 (67%) of 15 nodules on the portal-phase CT images; and high in four (17%), homogeneous in six (26%), and low in 13 (57%) of 23 nodules on the delayed-phase CT images. Signal intensity of nodules was high in 15 (94%) and homogeneous in one (6%) of 16 nodules on T1-weighted MR images and was homogeneous in seven (44%) and low in nine (56%) of 16 nodules on T2-weighted MR images. Vascularity of nodules was avascular in 14 (88%) and slightly vascular in two (12%) of 16 nodules. Conclusions: Hepatic dysplastic nodules show diverse imaging characteristics with different imaging techniques; however, common imaging findings of hepatic dysplastic nodules are low echo, low attenuation, and high, low, or homogeneous intensity on T1- and T2-weighted MR, and avascularity.

Direct Conversion of Adult Skin Fibroblasts to Endothelial Cells by Defined Factors

Background— Cell-based therapies to augment endothelial cells (ECs) hold great therapeutic promise. Here, we report a novel approach to generate functional ECs directly from adult fibroblasts. Methods and Results— Eleven candidate genes that are key regulators of endothelial development were selected. Green fluorescent protein (GFP)–negative skin fibroblasts were prepared from Tie2-GFP mice and infected with lentiviruses allowing simultaneous overexpression of all 11 factors. Tie2-GFP+ cells (0.9%), representing Tie2 gene activation, were detected by flow cytometry. Serial stepwise screening revealed 5 key factors (Foxo1, Er71, Klf2, Tal1, and Lmo2) that were required for efficient reprogramming of skin fibroblasts into Tie2-GFP+ cells (4%). This reprogramming strategy did not involve pluripotency induction because neither Oct4 nor Nanog was expressed after 5 key factor transduction. Tie2-GFP+ cells were isolated using fluorescence-activated cell sorting and designated as induced ECs (iECs). iECs exhibited endothelium-like cobblestone morphology and expressed EC molecular markers. iECs possessed endothelial functions such as Bandeiraea simplicifolia-1 lectin binding, acetylated low-density lipoprotein uptake, capillary formation on Matrigel, and nitric oxide production. The epigenetic profile of iECs was similar to that of authentic ECs because the promoters of VE-cadherin and Tie2 genes were demethylated. mRNA profiling showed clustering of iECs with authentic ECs and highly enriched endothelial genes in iECs. In a murine model of hind-limb ischemia, iEC implantation increased capillary density and enhanced limb perfusion, demonstrating the in vivo viability and functionality of iECs. Conclusions— We demonstrated the first direct conversion of adult fibroblasts to functional ECs. These results suggest a novel therapeutic modality for cell therapy in ischemic vascular disease.

Detection of pancreatic adenocarcinoma: relative value of arterial and late phases of spiral CT.

Abstract.Background: Spiral computed tomography (CT) allows the pancreas to be imaged during peak contrast levels owing to the capability of fast data acquisition. The objective of this study was to evaluate the relative value of the arterial and late phases of spiral CT for detecting pancreatic adenocarcinomas. Methods: Twenty-two patients with pathologically proved pancreatic adenocarcinomas underwent two-phase spiral CT. The CT scans were performed with 5 mm collimation and 5 mm/s table speed. Images during the arterial and late phases were obtained at 30- and 180-second delays, respectively. The images of the arterial phase were compared with those of the late phase in terms of tumor conspicuity from surrounding pancreatic parenchyma and tumor detectability by means of a 3-point grading system: 1 (poor), 2 (fair), and 3 (good). Results: In terms of tumor conspicuity from surrounding pancreatic parenchyma, 16 lesions (73%) were good, 5 lesions (23%) were fair, and 1 lesion (4%) was poor during the arterial phase, whereas 6 lesions (27%) were good, 9 lesions (41%) were fair, and 7 lesions (32%) were poor during the late phase (p= 0.0007). The arterial phase was superior to the late phase in 16 patients (73%) and equal in 6 patients (27%). For tumor detectability, 18 lesions (82%) were good, 3 lesions (14%) were fair, and 1 lesion (4%) was poor during the arterial phase, whereas 10 lesions (45%) were good, 7 lesions (32%) were fair, and 5 lesions (23%) were poor during the late phase (p= 0.0033). For detectability, the arterial phase was superior to the late phase in 14 patients (64%) and equal in 8 patients (36%). Conclusion: The arterial phase of spiral CT is superior to the late phase, which is equivalent to conventional CT for detecting pancreatic adenocarcinoma.

Peripheral cholangiocarcinoma: comparison of MRI with CT

To evaluate the clinical utility of computed tomography (CT) and magnetic resonance imaging (MRI) in the diagnosis of peripheral cholangiocarcinoma of the liver, 11 patients with pathologically proven peripheral cholangiocarcinoma were examined with both CT and MRI. On CT scans in 10 cases, the tumors appeared as irregular, low-attenuation masses with a wide variation in heterogeneity. Contrast enhancement of the tumors was mild in nine cases and moderate in one case, at the periphery. Tumor was not identified in one case. On T1-weighted MRIs, the tumors showed low intensity in eight cases and isointensity in three cases. On T2-weighted images, the tumors showed high intensity in all 11 cases. Focal dilatation of the intrahepatic bile ducts around the tumor was seen in one case on MRIs and in four cases on CT scans. Portal vein invasion of the tumors was seen in one case, and lymphadenopathy was seen in four cases on both MRIs and CT scans. MRI was slightly superior to CT in detecting the tumors, was inferior to CT in delineating focal ductal dilatation around the tumors, and was equal to CT in assessing extent of the tumors.

Combined hepatocellular and cholangiocarcinoma of the liver: Sonography, CT, Angiography, and Iodized-Oil CT with pathologic correlation

To evaluate the characteristics of combined hepatocellular and cholangiocarcinoma of the liver by imaging techniques, six patients (five male and one female), aged 46–60 years, with proved combined tumors were selected for this study from the review of 500 resected specimens of liver tumors. Images obtained from sonography, computed tomography (CT), angiography, and CT after intraarterial injection of iodized oil (iodized-oil CT) were retrospectively reviewed and correlated with the appearance of pathologic specimens. Sonographic findings were round or ovoid hypoechoic masses with central hyperechoic area (target appearance) in all patients. On CT scans, tumors were relatively well-defined low- and/or iso-attenuation masses in all patients. Angiography showed hypovascular masses in five patients. In one patient, the tumor appeared as a hypovascular mass with a central hypervascular area. On iodized-oil CT scans, all patients showed partial retention of iodized oil in tumors. Echogenicity in tumors at sonography or attenuation in tumors at CT could not be correlated with histologic difference in tumors at pathologic specimens. However, the hypervascular area at angiography and the compact retention areas of iodized oil at iodized-oil CT corresponded to portions of hepatocellular carcinoma within the combined tumor. On the basis of our results, imaging features, including target appearance at sonography, hypovascular mass with central hypervascular portions at angiography, and partial retention of iodized oil in tumors at iodized-oil CT, might be helpful in making accurate diagnosis of these rare tumors.

Biliary obstruction in metastatic disease: thin-section helical CT findings

AbstractBackground: We describe the thin-section helical computed tomographic (CT) findings of biliary obstruction caused by metastasis. Methods: Thin-section helical CT (5 mm slice thickness, 1:1 pitch, portal phase) and direct cholangiography in 50 consecutive patients with biliary obstruction caused by metastases were reviewed retrospectively by three radiologists. The primary sites were the stomach (n = 36), colon (n = 12), jejunum (n = 1), and uterus (n = 1). The level of biliary obstruction was analyzed with the Bismuth classification, and the CT findings of biliary obstruction were classified into six types: small (<2 cm) periductal masses, large (≥2 cm) periductal masses, extrinsic compression by a metastatic liver mass, high-attenuation intraductal mass, intrapancreatic mass, and no demonstrable lesion. Results: The level of biliary obstruction was the hilum in 18 patients (36%), the proximal common duct in 20 (40%), the distal common duct in five (10%), and the periampullary area in seven (14%). Of 18 hilar obstructions, tumor involvement of the secondary confluence of intrahepatic bile ducts was seen in 10 (right in six, left in one, and bilateral in three). Periductal masses were seen in 68% (small in 18, large in 16). In one patient (2%), a large metastatic mass of the liver resulted in extrinsic compression and biliary obstruction. Lesions mimicking primary biliary or pancreatic tumor were seen in four, respectively. In seven, we found no obstructing lesion on CT. Conclusion: Biliary obstruction in patients with known primary malignancies can show atypical patterns mimicking primary pancreatobiliary malignancies on thin-section helical CT.