A three-day course of dexamethasone therapy to prevent chronic lung disease in ventilated neonates: a randomized trial.

BACKGROUND: Although several trials of early dexamethasone therapy have been completed to determine if such therapy would reduce mortality and chronic lung disease (CLD) in infants with respiratory distress, optimal duration and side effects of such therapy remain unknown. PURPOSE: The purpose of this study was: 1) to determine if a 3-day course of early dexamethasone therapy would reduce CLD and increase survival without CLD in neonates who received surfactant therapy for respiratory distress syndrome and 2) to determine adverse effects associated with such therapy. DESIGN: This was a prospective multicenter randomized trial comparing a 3-day course of dexamethasone therapy beginning at 24 to 48 hours of life to placebo therapy. Two hundred forty-one neonates (dexamethasone n = 118, placebo n = 123), who weighed between 500 g and 1500 g, received surfactant therapy, and were at significant risk for CLD or death using a model to predict CLD or death at 24 hours of life, were enrolled in the trial. Infants randomized to receive early dexamethasone were given 6 doses of dexamethasone at 12-hour intervals beginning at 24 to 48 hours of life. The primary outcomes compared were survival without CLD and CLD. CLD was defined by the need for supplemental oxygen at the gestational age of 36 weeks. Complication rates and adverse effects of study drug therapy were also compared. RESULTS: Neonates randomized to early dexamethasone treatment were more likely to survive without CLD (RR: 1.3; 95% CI: 1.03, 1.7) and were less likely to develop CLD (RR: 0.6; CI: 0.3, 0. 98). Mortality rates were not significantly different. Subsequent dexamethasone therapy use was less in early dexamethasone-treated neonates (RR: 0.8; CI: 0.7, 0.96). Very early (

Studies with a spontaneous mouse tumor. I. Growth in normal mice and response to Corynebacterium parvum.

Growth of isogeneic transplants of a spontaneous murine adenocarcinoma, which is virtually devoid of tumour-specific transplantation antigens, is inhibited by i.v. injection of C. parvum 3 days after tumour inoculation, or by mixing a small dose of C. parvum with the tumour inoculum. Moreover, the therapeutic effect of cyclophosphamide, followed by i.v. or i.p. injection of C. parvum 5 days later, on established transplants of the same tumour is greater than that of cyclophosphamide alone. These findings are consistent with the hypothesis that in both situations (i.e. before the appearance of a palpable tumour and after reduction of an established tumour transplant with cyclophosphamide) the effect of C. parvum is largely due to activation of macrophages or macrophage precursors. They have the important practical implication that adjuvant therapy with C. parvum may be of value, even with tumours which are devoid of TSTA.

Modification of the effect of C. parvum on macrophage activity and tumour growth by X-irradiation.

The radiosensitivity of three forms of response to injection of C. parvum in mice has been investigated. The increase in phagocytin index evoked by IP or IV injection of 0.7 mg C. parvum (but not that evoked by 1.4 mg) was reduced but not abolished in mice given 350-500 rad whole-body irradiation 4 days before C. parvum injection. Irradiation (500-1,000 rad) 4 days after C. parvum injection had no such effect. The antitumour cytotoxicity in vitro of PE and spleen cells from C. parvum-treated mice was abolished by irradiation of the cell donor (400-800 rad) 4 days before C. parvum injection, but was not reduced by irradiation (800 rad) of the cell donor 4 days after C. parvum injection or of the effector cells in vitro. The antitumour response to systemic (IP) injection of C. parvum was reduced by 350-500 rad whole-body irradiation, irrespective of whether this was given 4 days before or 4 days after C. parvum injection. The response to intratumour injection of C. parvum was even more radiosensitive. It has been suggested in previous papers from this laboratory that the antitumour effect of C. parvum is related to its capacity to stimulate macrophage activity, although in addition T lymphocytes are necessary for local injection to be effective and non-T lymphocytes may be concerned in the response to both local and systemic injection. The present results in no way conflict with this view. They suggest in addition that the effect of C. parvum on the macrophage system is, to a considerable extent, due to stimulation of macrophage precursors to differentiate into actively phagocytic and cytotoxic mature cells.

Effect of C. Parvum on immunization with irradiated tumour cells.

S.c. injection of tumour cells or small pieces of tumour irradiated to a dose of 22,000 rad evoked resistance to live challenge with the same tumour (a CBA strain fibrosarcoma induced with methylcholanthrene) 14 days later. This resistance was, however, over-ridden if the challenging inoculum was sufficiently large, and did not develop if the cells were irradiated to 100,000 rad. The resistance evoked by injection of 10(6) irradiated tumour cells was impaired by i.p. injection of 1-4 mg C. parvum 5 days before, and virtually abolished by a similar injection 11 days after, the irradiated cells. The effect of s.c. injection of a mixture of 10(6) irradiated cells and C. parvum 14 days before live challenge depended on the dose of C. parvum. With 0-7 mg the development of resistance was largely but not completely abrogated; 0-35 mg resulted in a lesser degree of abrogation, and 0-09 mg or 0-02 mg had little or no effect.