Andrew M. Kopelman

The targeted inactivation of oncogenes offers a rational therapeutic approach for the treatment of cancer. However, the therapeutic inactivation of a single oncogene has been associated with tumor recurrence. Therefore, it is necessary to develop strategies to override mechanisms of tumor escape from oncogene dependence. We report here that the targeted inactivation of MYC is sufficient to induce sustained regression of hematopoietic tumors in transgenic mice, except in tumors that had lost p53 function. p53 negative tumors were unable to be completely eliminated, as demonstrated by the kinetics of tumor cell elimination revealed by bioluminescence imaging. Histological examination revealed that upon MYC inactivation, the loss of p53 led to a deficiency in thrombospondin-1 (TSP-1) expression, a potent antiangiogenic protein, and the subsequent inability to shut off angiogenesis. Restoration of p53 expression in these tumors re-established TSP-1 expression. This permitted the suppression of angiogenesis and subsequent sustained tumor regression upon MYC inactivation. Similarly, the restoration of TSP-1 alone in p53 negative tumors resulted in the shut down of angiogenesis and led to sustained tumor regression upon MYC inactivation. Hence, the complete regression of tumor mass driven by inactivation of the MYC oncogene requires the p53-dependent induction of TSP-1 and the shut down of angiogenesis. Notably, overexpression of TSP-1 alone did not influence tumor growth. Therefore, the combined inactivation of oncogenes and angiogenesis may be a more clinically effective treatment of cancer. We conclude that angiogenesis is an essential component of oncogene addiction.

BACKGROUND: The Emergency Medical Treatment and Active Labor Act (EMTALA) effectively requires Level I trauma centers (TC) to accept all transfers for a higher level of care if capacity exists. We hypothesized that EMTALA would burden a Level I TC by a selective referral of a poor payer mix of primarily nonoperative patients. METHODS: All transfer calls (December 2003 and September 2005) to our Level I TC are handled by a dedicated transfer center. Calls were reviewed for age, surgical service requested, and outcome of request. The trauma registry was queried to compare Injury Severity Scale (ISS) score, hospital stay (LOS), operations, mortality, and payer status for transfer and primary catchment patients. RESULTS: In all, 821 calls were received; 77 calls were cancelled by the referring hospital and 52 were for consultation only. Of the 692 transfer requests, 534 (77%) were accepted, 134 (19%) were denied for no capacity, and only 24 (4%) were declined by TC as not clinically indicated. Transferred patients were younger (32.0 +/- 1.49 versus 38.9 +/- 0.51, p < 0.05), had similar ISS scores (13.6 +/- 0.62 versus 13.7 +/- 0.26) and LOS (7.0 +/- 0.70 versus 7.4 +/- 0.25), but were somewhat more likely to require an operation than direct admissions (58% versus 51%, p < 0.05). Although trauma (24%) and neurosurgery (24%) were the most commonly requested services, followed by orthopedics (20%), orthopedics accounted for 60% of operations on transferred patients compared with 10% to 13% for trauma and neurosurgery (mostly spine). There was no difference in the payer status of transfer and direct admit patients. CONCLUSIONS: Contrary to our assumptions, EMTALA patients had an identical payer mix and similar operative need compared with our primary catchment patients. They do represent a large additional patient load (20% of admissions) and differentially impact specialists, mostly operative for orthopedics and complex nonoperative care for trauma and neurosurgery. These data suggest that the primary motivations for transfer are specialist availability and complexity of care rather than financial concerns. As TCs provide backup specialty call coverage for a wide geographic area, this further supports the need for trauma systems development.