Shockwave and Non-transfemoral Transcatheter Aortic Valve Replacement

Transcatheter aortic valve replacement (TAVR) has become a widely adopted treatment modality for severe aortic stenosis. Transfemoral access is the approach of choice; however, approximately 25% of patients undergoing TAVR also have concomitant peripheral arterial disease. The recent advent of intravascular lithotripsy has enabled preservation of transfemoral access in some patients; although, a proportion still require alternative, non-femoral access. Alternative access sites can be broadly categorized into transthoracic and peripheral, facilitated by surgical or percutaneous techniques. In this review, the technical details and clinical outcomes of various TAVR accesses are discussed. Initially, transthoracic approaches were most common, but recently, the trend has been toward alternative peripheral access due to superior outcomes. Although there are no randomized data to support all the alternative access sites, the experiences reported provide available options for a large portion of patients to be candidates for TAVR. The intervention site should be selected by a multidisciplinary heart team based on patient anatomical factors and institutional expertise

Percutaneous hepatic perfusion with melphalan for unresectable liver metastasis

Percutaneous hepatic perfusion (PHP) is an investigative technique for treating patients with diffuse unresectable metastatic liver disease. The technique has been clinically evaluated and shows great treatment potential for regional therapy to the liver. The advantage of PHP lies in its minimally invasive approach and ability to be repeated when compared to isolated hepatic perfusion. In a literature search, 135 publications were screened and 16 of these publications, including clinical trials and reviews, contributed to this review of PHP with melphalan. Melphalan is an alkylating agent that, when used as the chemotherapeutic agent in PHP, has shown potential for significant control of tumor burden in the liver, especially in metastatic ocular melanoma. In the current landscape of liver directed therapy, PHP is a viable option for those with unresectable metastatic disease to the liver. This article will focus on the technical aspects of PHP and describe the current data available from clinical trials, including outcomes of patients treated with this minimally invasive approach

Right Coronary Aneurysm with Coronary Arteriovenous Fistula to Right Atrium

<p>A 56-year-old man presented with shortness of breath and palpitations. Workup and evaluation revealed paroxysmal atrial fibrillation, severe tricuspid regurgitation, and a giant right coronary aneurysm with an arteriovenous fistula to the right atrium. An echocardiogram revealed an aneurysm of the proximal right coronary artery. Cardiac catheterization and cardiac magnetic resonance imaging showed the aneurysm coursing between the right pulmonary artery and the ascending aorta. The caliber of the right coronary artery distal to the aneurysm was normal.<br> A median sternotomy was performed and the pericardium was opened to encounter the proximal right coronary aneurysm. The superior vena cava was looped to allow for exclusion of venous return. Direct cannulation of the aorta and percutaneous access of the femoral vein were performed to place the patient on cardiopulmonary bypass. Further dissection revealed the giant aneurysm between the aorta, right pulmonary artery, and superior vena cava, with an apparent arteriovenous fistula between the right coronary aneurysm and the right atrium. The shunted blood flow coursed from the aorta, to the right coronary aneurysm, to the right atrium.<br> After the heart was arrested and the patient placed on cardiopulmonary bypass, the normal right coronary artery distal to the aneurysm was dissected, allowing for a reverse saphenous vein to be grafted. The right coronary artery between the aneurysm and the graft was ligated. The proximal right coronary artery was further identified and ligated at the aorta. Attention was then turned to the right atrium, which was opened to identify the entry of the arteriovenous fistula. Additionally, the proximal right coronary artery aneurysm sac was opened and followed down through the giant aneurysm to the right atrium. A probe was passed to delineate the flow through the fistula. A bovine pericardium patch was sewn from within the right atrium to close the fistula. <br> The severe tricuspid regurgitation discovered during preoperative workup was managed with the placement of a tricuspid annuloplasty ring. A left-sided pulmonary vein maze procedure was performed for the atrial arrhythmia, and was accompanied by the placement of a left atrial appendage clip. The proximal vein graft was then anastomosed to the aorta, and the aortic clamp was released. The right coronary aneurysm sac and giant aneurysm were oversewn. The patient was taken off of cardiopulmonary bypass with restoration of normal anatomic blood flow.<br> In conclusion, this video demonstrates the presentation, diagnosis, and surgical treatment of a large complex right coronary artery aneurysm with an arteriovenous fistula to the right atrium. The surgical treatment was ligation and exclusion of the aneurysm, with coronary artery bypass to the distal right coronary artery, and patch repair of the right atrium. The patient had an uneventful postoperative course with a full recovery.</p

ASXL3 is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer

In this study, we generated induced pluripotent stem cells (iPSC) from normal human small airway epithelial cells (SAEC) to investigate epigenetic mechanisms of stemness and pluripotency in lung cancers. We documented key hallmarks of reprogramming in lung iPSC (Lu-iPSC) that coincided with modulation of more than 15,000 genes relative to parental SAEC. Of particular novelty, we identified the PRC2-associated protein, ASXL3 which was markedly upregulated in Lu-iPSC and small cell lung cancer (SCLC) lines and clinical specimens. ASXL3 overexpression correlated with increased genomic copy number in SCLC lines. ASXL3 silencing inhibited proliferation, clonogenicity and teratoma formation by Lu-iPSC, and diminished clonogenicity and malignant growth of SCLC cells in-vivo. Collectively, our studies validate the utility of the Lu-iPSC model for elucidating epigenetic mechanisms contributing to pulmonary carcinogenesis, and highlight ASXL3 as a novel candidate target for SCLC therapy

ASXL3 is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer

In this study, we generated induced pluripotent stem cells (iPSC) from normal human small airway epithelial cells (SAEC) to investigate epigenetic mechanisms of stemness and pluripotency in lung cancers. We documented key hallmarks of reprogramming in lung iPSC (Lu-iPSC) that coincided with modulation of more than 15,000 genes relative to parental SAEC. Of particular novelty, we identified the PRC2-associated protein, ASXL3 which was markedly upregulated in Lu-iPSC and small cell lung cancer (SCLC) lines and clinical specimens. ASXL3 overexpression correlated with increased genomic copy number in SCLC lines. ASXL3 silencing inhibited proliferation, clonogenicity and teratoma formation by Lu-iPSC, and diminished clonogenicity and malignant growth of SCLC cells in-vivo. Collectively, our studies validate the utility of the Lu-iPSC model for elucidating epigenetic mechanisms contributing to pulmonary carcinogenesis, and highlight ASXL3 as a novel candidate target for SCLC therapy

Identification of Novel Targets for Lung Cancer Therapy Using an Induced Pluripotent Stem Cell Model

RATIONALE: Despite extensive studies, the genetic and epigenetic mechanisms that mediate initiation and progression of lung cancers have not been fully elucidated. Previously, we have demonstrated that via complementary mechanisms, including DNA methylation, polycomb repressive complexes, and noncoding RNAs, cigarette smoke induces stem-like phenotypes that coincide with progression to malignancy in normal respiratory epithelia as well as enhanced growth and metastatic potential of lung cancer cells. OBJECTIVES: To further investigate epigenetic mechanisms contributing to stemness/pluripotency in lung cancers and potentially identify novel therapeutic targets in these malignancies, induced pluripotent stem cells were generated from normal human small airway epithelial cells. METHODS: Lung induced pluripotent stem cells were generated by lentiviral transduction of small airway epithelial cells of OSKM (Yamanaka) factors (octamer-binding transcription factor 4 [Oct4], sex-determining region Y box 2 [SOX2], Kruppel-like factor 4 [KLF4], and MYC proto-oncogene, bHLH transcription factor [MYC]). Western blot, real-time polymerase chain reaction, and chromatin immunoprecipitation sequencing analysis were performed. RESULTS: The lung induced pluripotent stem cells exhibited hallmarks of pluripotency, including morphology, surface antigen and stem cell gene expression, in vitro proliferation, and teratoma formation. In addition, lung induced pluripotent stem cells exhibited no chromosomal aberrations, complete silencing of reprogramming transgenes, genomic hypermethylation, upregulation of genes encoding components of polycomb repressive complex 2, hypermethylation of stem cell polycomb targets, and modulation of more than 15,000 other genes relative to parental small airway epithelial cells. Additional sex combs like-3 (ASXL3), encoding a polycomb repressive complex 2-associated protein not previously described in reprogrammed cells, was markedly upregulated in lung induced pluripotent stem cell as well as human small cell lung cancer lines and specimens. Overexpression of the additional sex combs like-3 gene correlated with increased genomic copy number in small cell lung cancer lines. Knock-down of the additional sex combs like-3 gene inhibited proliferation, clonogenicity, and teratoma formation by lung induced pluripotent stem cells and significantly diminished in vitro clonogenicity and growth of small cell lung cancer cells in vivo. CONCLUSIONS: Collectively, these studies highlight the potential utility of this lung induced pluripotent stem cell model for elucidating epigenetic mechanisms contributing to pulmonary carcinogenesis and suggest that additional sex combs like-3 is a novel target for small cell lung cancer therapy