Global intracoronary infusion of allogeneic cardiosphere-derived cells improves ventricular function and stimulates endogenous myocyte regeneration throughout the heart in swine with hibernating myocardium.

BACKGROUND: Cardiosphere-derived cells (CDCs) improve ventricular function and reduce fibrotic volume when administered via an infarct-related artery using the "stop-flow" technique. Unfortunately, myocyte loss and dysfunction occur globally in many patients with ischemic and non-ischemic cardiomyopathy, necessitating an approach to distribute CDCs throughout the entire heart. We therefore determined whether global intracoronary infusion of CDCs under continuous flow improves contractile function and stimulates new myocyte formation. METHODS AND RESULTS: Swine with hibernating myocardium from a chronic LAD occlusion were studied 3-months after instrumentation (n = 25). CDCs isolated from myocardial biopsies were infused into each major coronary artery (∼ 33 × 10(6) icCDCs). Global icCDC infusion was safe and while ∼ 3% of injected CDCs were retained, they did not affect ventricular function or myocyte proliferation in normal animals. In contrast, four-weeks after icCDCs were administered to animals with hibernating myocardium, %LADWT increased from 23 ± 6 to 51 ± 5% (p<0.01). In diseased hearts, myocyte proliferation (phospho-histone-H3) increased in hibernating and remote regions with a concomitant increase in myocyte nuclear density. These effects were accompanied by reductions in myocyte diameter consistent with new myocyte formation. Only rare myocytes arose from sex-mismatched donor CDCs. CONCLUSIONS: Global icCDC infusion under continuous flow is feasible and improves contractile function, regresses myocyte cellular hypertrophy and increases myocyte proliferation in diseased but not normal hearts. New myocytes arising via differentiation of injected cells are rare, implicating stimulation of endogenous myocyte regeneration as the primary mechanism of repair.

An Atypical Presentation with Diagnostic Challenge of a Large Cell Neuroendocrine Cancer of Lung: A Case Report and Review of the Literature.

Large-cell neuroendocrine carcinomas (LCNECs) are relatively rare and aggressive neoplasms of the lung with very poor prognosis. Even though they are included in the classification of nonsmall cell carcinomas, they have a biological behaviour and physiological response to treatment more like small cell carcinomas of lung. We report an atypical case presentation of LCNEC in a 51-year-old gentleman who presented with diffuse metastases to the thoracic and lumbar spine, brain, and liver, posing a diagnostic challenge. The primary small central lung tumor was in close proximity to major vessels, rendering a biopsy of the primary cancer challenging and nearly impossible. The final diagnosis was established through immunohistochemistry staining and examination of liver biopsy from a metastatic lesion. We also included a review of the current literature pertinent to LCNEC, as well as the important role of tumor markers plus immunohistochemistry profiles in determining the origin of unknown primary tumors in such difficult patient presentations.