Faculty Bibliography

The number of candidates awaiting liver transplantation continues to exceed the available donor organ pool. This steadily increasing donor organ shortage calls for the widening of selection criteria for potential donor organs. Strategies to increase the number of liver allografts include liver splitting, use of donors over 70 years, use of steatotic donor livers, and reutilization of liver allografts after brain death of the first recipient. We report the successful use of a polycystic donor liver and review the experience with this donor population. We propose that the selective use of polycystic donor livers containing small (<5 cm) cysts with preserved liver parenchyma is safe and appropriate.

BACKGROUND:Patients with primary hyperparathyroidism who undergo minimally invasive parathyroidectomy (MIP) may have postoperative symptoms of hypocalcemia or secondary hyperparathyroidism. This study sought to identify factors predictive of these events. METHODS:Between 1998 and 2004, 190 patients with primary hyperparathyroidism underwent MIP with excision of a single adenoma. Age, gender, race, prior head and neck surgery, use of preoperative thyroid hormone or calcium-channel blockers, preoperative levels of calcium, 25-hydroxyvitamin D (25[OH]D) and intact parathyroid hormone (iPTH), the presence of osteopenia or osteoporosis, intraoperative iPTH levels, and adenoma weight were evaluated by univariate analysis as predictors of postoperative symptoms of hypocalcemia and secondary hyperparathyroidism. RESULTS:None of the following were predictors of postoperative symptoms of hypocalcemia: age, gender, race, prior head and neck surgery, preoperative medications, preoperative calcium and iPTH levels, osteopenia or osteoporosis, intraoperative iPTH levels, or adenoma weight. However, patients with postoperative symptoms of hypocalcemia had significantly lower preoperative 25[OH]D levels (P = .01). Further, higher preoperative iPTH levels (P < .01) and lower preoperative 25[OH]D levels (P = .05) were associated with secondary hyperparathyroidism postoperatively. CONCLUSIONS:A low preoperative 25[OH]D level is associated with postoperative symptoms of hypocalcemia and secondary hyperparathyroidism in patients undergoing MIP. One might consider instituting empiric calcium supplementation postoperatively in patients with low 25[OH]D levels.

Cell-cycle dysregulation is a hallmark of tumor cells. The ability of normal cells to undergo cell-cycle arrest after damage to DNA is crucial for the maintenance of genomic integrity. The biochemical pathways that stop the cell cycle in response to cellular stressors are called checkpoints. Defective checkpoint function results in genetic modifications that contribute to tumorigenesis. The regulation of checkpoint signaling also has important clinical implications because the abrogation of checkpoint function can alter the sensitivity of tumor cells to chemotherapeutics. Here, we provide an overview of the mechanisms that regulate the cell cycle, current anticancer therapies that target checkpoint signaling pathways, and strategies for the development of novel chemotherapeutic agents.

Although toxicants may initiate cell damage or stress, the cellular proteins that are involved in control of cell cycle and apoptosis are the final arbiters of cell fate. The biochemical pathways that restrain cell cycle transition and/or induce cell death after stress are known as cell cycle checkpoints. These checkpoints maintain the fidelity of DNA replication, repair, and division. Herein, select cell cycle checkpoint signaling pathways will be discussed and how different components of these pathways are regulated by exogenous and endogenous agents, with focus on the p53 tumor suppressor signaling. The p53 protein is known to play a key role in growth arrest and apoptosis after cell stress, primarily through its ability to regulate the transcription of select downstream target genes in the cell. Further elucidation of the signaling pathways that control growth arrest and apoptosis will continue to provide insights to the complex cellular responses to environmental toxicants.

OBJECTIVE:To determine the mechanism of action of paclitaxel (Taxol) and carboplatin in cell lines of head and neck squamous cell carcinoma (HNSCC). DESIGN/METHODS:Four HNSCC cell lines were treated with paclitaxel and carboplatin, alone or in combination, and evaluated for cell-cycle position by means of flow cytometry, for molecular determinants of cell cycle by means of Western blotting and kinase analysis, and for anchorage-independent growth by means of soft-agar assays. RESULTS:Paclitaxel was more effective at inducing apoptosis and inhibiting anchorage-independent cell growth, compared with carboplatin. The activity of paclitaxel was correlated with an elevation of cyclin B1/CDC2 activity, prolonged mitotic arrest, and Bcl-2 phosphorylation. In contrast, carboplatin arrested cells before mitosis. Combination treatment with both agents, simultaneously or sequentially, was more effective at inhibiting cell growth than either single agent. Cellular outcome was the same regardless of which drug was used first. The order of addition of these 2 drugs differentially affected cell-cycle position. Paclitaxel pretreatment arrested cells in mitosis, whereas carboplatin pretreatment or cotreatment resulted in premitotic arrest. CONCLUSIONS:To our knowledge, this study is the first to explore how paclitaxel and carboplatin, alone or in combination, differentially affect cell-cycle checkpoint response and HNSCC cell growth. These results provide molecular validation for the current clinical use of both drugs in combination and set the stage for analyses of patient tumor specimens.