Disclosures of conflicts of interest in psychiatric review articles.

To characterize disclosures of conflicts of interest in review articles in psychiatry, we identified 285 reviews from 10 high-impact journals in psychiatry and 2 in general medicine. Disclosures were reliably coded as biotechnology/pharmaceutical/other material interests, nonprofit/government, communication companies, or other. The authors in both types of journals frequently reported industry ties. However, the reviews in the psychiatric journals were significantly less likely to include industry-related disclosures (32% of the reviews; 18% of the authors) compared with the general medical journals (64% of the articles; 40% of the authors). The most common types of industry-related disclosures were for consulting, research support, and speaking fees. Disclosures seemed to be of limited utility in helping readers assess possible biases because the nature and the extent of the relationships being disclosed were often unclear. Efforts to screen out authors with significant financial relationships pertaining to the topic under review may be more effective than are disclosures in protecting the integrity of the medical literature.

CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation.

Oncogene addiction is thought to occur cell autonomously. Immune effectors are implicated in the initiation and restraint of tumorigenesis, but their role in oncogene inactivation-mediated tumor regression is unclear. Here, we show that an intact immune system, specifically CD4(+) T cells, is required for the induction of cellular senescence, shutdown of angiogenesis, and chemokine expression resulting in sustained tumor regression upon inactivation of the MYC or BCR-ABL oncogenes in mouse models of T cell acute lymphoblastic lymphoma and pro-B cell leukemia, respectively. Moreover, immune effectors knocked out for thrombospondins failed to induce sustained tumor regression. Hence, CD4(+) T cells are required for the remodeling of the tumor microenvironment through the expression of chemokines, such as thrombospondins, in order to elicit oncogene addiction.

Requests for 692 transfers to an academic level I trauma center: implications of the emergency medical treatment and active labor act.

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.

Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch.

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.

MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer.

Hepatocellular carcinoma is generally refractory to clinical treatment. Here, we report that inactivation of the MYC oncogene is sufficient to induce sustained regression of invasive liver cancers. MYC inactivation resulted en masse in tumour cells differentiating into hepatocytes and biliary cells forming bile duct structures, and this was associated with rapid loss of expression of the tumour marker alpha-fetoprotein, the increase in expression of liver cell markers cytokeratin 8 and carcinoembryonic antigen, and in some cells the liver stem cell marker cytokeratin 19. Using in vivo bioluminescence imaging we found that many of these tumour cells remained dormant as long as MYC remain inactivated; however, MYC reactivation immediately restored their neoplastic features. Using array comparative genomic hybridization we confirmed that these dormant liver cells and the restored tumour retained the identical molecular signature and hence were clonally derived from the tumour cells. Our results show how oncogene inactivation may reverse tumorigenesis in the most clinically difficult cancers. Oncogene inactivation uncovers the pluripotent capacity of tumours to differentiate into normal cellular lineages and tissue structures, while retaining their latent potential to become cancerous, and hence existing in a state of tumour dormancy.