Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis.

BACKGROUND: Intimal smooth muscle cells (SMCs) contribute to the foam cell population in arterial plaque, and express lower levels of the cholesterol exporter ATP-binding cassette transporter A1 (ABCA1) in comparison with medial arterial SMCs. The relative contribution of SMCs to the total foam cell population and their expression of ABCA1 in comparison with intimal monocyte-derived macrophages, however, are unknown. Although the expression of macrophage markers by SMCs following lipid loading has been described, the relevance of this phenotypic switch by SMCs in human coronary atherosclerosis has not been determined. METHODS AND RESULTS: Human coronary artery sections from hearts explanted at the time of transplantation were processed to clearly delineate intracellular and extracellular lipids and allow costaining for cell-specific markers. Costaining for oil red O and the SMC-specific marker SM α-actin of foam cell-rich lesions revealed that 50±7% (average±standard error of the mean, n=14 subjects) of total foam cells were SMC derived. ABCA1 expression by intimal SMCs was significantly reduced between early and advanced atherosclerotic lesions, with no loss in ABCA1 expression by myeloid lineage cells. Costaining with the macrophage marker CD68 and SM α-actin revealed that 40±6% (n=15) of CD68-positive cells originated as SMCs in advanced human coronary atherosclerosis. CONCLUSIONS: These findings suggest SMCs contain a much larger burden of the excess cholesterol in human coronary atherosclerosis than previously known, in part, because of their relative inability to release excess cholesterol via ABCA1 in comparison with myeloid lineage cells. Our results also indicate that many cells identified as monocyte-derived macrophages in human atherosclerosis are in fact SMC derived.

Defining postoperative ileus and associated risk factors in patients undergoing radical cystectomy with an Enhanced Recovery After Surgery (ERAS) program.

INTRODUCTION: Postoperative ileus (POI) is a common complication of radical cystectomy (RC), occurring in 1.6-23.5% of cases. It is defined heterogeneously in the literature. POI increases hospital length of stay and postoperative morbidity. Factors such as age, epidural use, length of procedure, and blood loss may impact POI. In this study, we aimed to evaluate risk factors that contribute to POI in a cohort of patients managed with a comprehensive Enhanced Recovery After Surgery (ERAS) protocol. METHODS: A retrospective review of consecutive patients who underwent RC from March 2015 to December 2016 at Vancouver General Hospital was performed. POI was defined a priori as insertion of nasogastric tube for nausea or vomiting, or failure to advance to a solid diet by the seventh postoperative day. To illustrate heterogeneity in previous studies, we also evaluated POI using other previously reported definitions in the RC literature. The influence of potential risk factors for POI, including patient comorbidities, American Society of Anesthesiologists score, gender, age, prior abdominal surgery or radiation, length of operation, diversion type, extent of lymph node dissection, removal date of analgesic catheter, blood loss, and fluid administration volume was analyzed. RESULTS: Thirty-six (27%) of 136 patients developed POI. Using other previously reported definitions for POI, the incidence ranged from <1-51%. Node-positive status and age at surgery were associated with POI on univariate analysis but not multivariable analysis. CONCLUSIONS: A large range of POI incidence was observed using previously published definitions of POI. We advocate for a standardized definition of POI when evaluating RC outcomes. POI occurs frequently even with a comprehensive ERAS protocol, suggesting that additional measures are needed to reduce the rate of POI.

Emerging intravesical therapies for the management of bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer: Charting a path forward.

Management of patients with bacillus Calmette-Guérin (BCG)-unresponsive, high-risk, non-muscle-invasive bladder cancer (NMIBC) presents a formidable clinical challenge that requires urologists to weigh the competing risks of progression during further intravesical therapy vs. the morbidity of radical cystectomy. The prognosis of high-risk NMIBC recurring after BCG depends on the adequacy of prior BCG, timing of recurrence, and tumor histology. The standard of care is currently radical cystectomy, as effective salvage intravesical therapy has not been established. The development of bladder-sparing treatments has been hampered to date by inconsistent definitions of BCG failure and difficulties in identifying appropriate control treatments in clinical trials. Despite these limitations, the spectrum of salvage therapy is expanding to include enhanced intravesical chemo-, gene, and immuno-therapies. In this review, we provide an overview of these emerging agents in the context of our current understanding of BCG failure and the unique considerations for clinical trial design in this disease state.