Possible benefit of doxorubicin treatment in patients with refractory germ cell cancer

Forty patients with germ cell cancer (GCC) refractory to vinblastine, cisplatin, and bleomycin therapy were treated with etoposide (E), cisplatin +/- bleomycin +/- doxorubicin and were evaluated retrospectively to determine response to treatment. Thirty cancers were primary testicular and ten extragonadal in origin. Fifty-five percent (22/40 patients) of the group responded to therapy. Eight of 40 (20%) patients had complete responses (CR) and 14 of 40 (35%) had partial responses (PR). Seven of 30 (23%) patients with a testes primary had a CR in contrast to 1 of 10 patients with extragonadal origin cancer. Six of eight patients (75%) having a CR received doxorubicin in combination, while only 2 of 18 (11%) patients having no response were treated with a doxorubicin-combining regimen. Of the entire group, 12 of 14 patients (86%) treated with doxorubicin for the first time responded to therapy compared to 10 to 26 patients (38.5%) not receiving doxorubicin (P = 0.009 Fisher's exact test). Myelosuppression was more frequent in patients treated with doxorubicin (87%) than in those treated without doxorubicin (70%). No increased frequency of hospitalization was required and no treatment-related fatalities occurred. Salvage therapy of patients with GCC appears to be improved when doxorubicin is added to etoposide, cisplatin, and bleomycin.     

Make or buy: HMOs' contracting arrangements for mental health care

Many health maintenance organizations (HMOs) are contracting with external vendors for mental health care, rather than maintaining an internal mental health department. We develop a framework for analyzing HMOs' contracting choices, rooted in transaction cost economics. Applying this framework, external contracting seems most likely to appeal to smaller, newer HMOs and those located in areas with multiple vendors. Pressure from value-oriented buyers may make it harder for HMOs to provide mental health internally, without costly reforms to their product. HMO contracting arrangements deserve further study, given their implications for cost and the quality of care.Support for this research was provided by the NIMH training grant and by the Robert Wood Johnson Foundation. The authors thank Suzanne Gelber, Lucille C. Kihlstrom, Tom McGuire and Larry Southwick for helpful comments, and Richard Frank for useful discussions.A previous draft of this paper was presented at the NIMH Conference on Mental Health Services Research, September 1995, Bethesda, MD.     

Measuring hospital mortality rates: are 30-day data enough? Ischemic Heart Disease Patient Outcomes Research Team.

OBJECTIVE. We compare 30-day and 180-day postadmission hospital mortality rates for all Medicare patients and those in three categories of cardiac care: coronary artery bypass graft surgery, acute myocardial infarction, and congestive heart failure. DATA SOURCES/COLLECTION. Health Care Financing Administration (HCFA) hospital mortality data for FY 1989. STUDY DESIGN. Using hospital level public use files of actual and predicted mortality at 30 and 180 days, we constructed residual mortality measures for each hospital. We ranked hospitals and used receiver operating characteristic (ROC) curves to compare 0-30, 31-180, and 0-180-day postadmission mortality. PRINCIPAL FINDINGS. For the admissions we studied, we found a broad range of hospital performance when we ranked hospitals using the 30-day data; some hospitals had much lower than predicted 30-day mortality rates, while others had much higher than predicted mortality rates. Data from the time period 31-180 days postadmission yield results that corroborate the 0-30 day postadmission data. Moreover, we found evidence that hospital performance on one condition is related to performance on the other conditions, but that the correlation is much weaker in the 31-180-day interval than in the 0-30-day period. Using ROC curves, we found that the 30-day data discriminated the top and bottom fifths of the 180-day data extremely well, especially for AMI outcomes. CONCLUSIONS. Using data on cumulative hospital mortality from 180 days postadmission does not yield a different perspective from using data from 30 days postadmission for the conditions we studied.     

Adherence of L1210 murine leukemia cells to sephacryl- aminopropylcobalamin beads treated with transcobalamin-II

Sephacryl beads containing an immobilized aminopropylcobalamin- transcobalamin-II complex serve as foci for the adherence of L1210 murine leukemia cells. Bead-cell interaction does not occur when (A) nonderivatized beads are used; (B) transcobalamin-II is omitted or presaturated with cyanocobalamin in the preparation of the bead complex; (C) intrinsic factor replaces transcobalamin-II; and (D) the complex is removed from beads by photolysis. These observations suggest that adherence results from the ability of transcobalamin-II to form a bridge between immobilized cobalamin on the bead and receptors in the plasma membrane of the cell.     

Activation of the CPP32 protease in apoptosis induced by 1-beta-D- arabinofuranosylcytosine and other DNA-damaging agents

The response of human myeloid leukemia cells to treatment with 1-beta- arabinofuranosylcytosine (ara-C) includes the induction of apoptosis. Ara-C induced apoptosis is associated with proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) and protein kinase C (PKC) delta. However, the signals involved in this response are unknown. The present studies show that ara-C treatment of U-937 cells is associated with induction of a protease activity that cleaves the tetrapeptides Ac-DEVD- pNA and Ac-DMOD-pNA found at the cleavage sites of PARP and PKC delta, respectively. The ara-C-induced protease activity was sensitive to overexpression of the anti-apoptotic protein Bcl-xL and the baculovirus protein p35. By contrast, overexpression of the cowpox virus protein CrmA blocked apoptosis induced by engagement of the Fas receptor but not that induced by ara-C. CrmA overexpression also had no detectable effect on ara-C-induced cleavage of PKC delta. The results further show that ara-C induces activation of the CPP32 protease by a CrmA- insensitive and p35-sensitive mechanism. Similar results were obtained with cisplatinum, etoposide, and camptothecin. These findings indicate that ara-C and other DNA-damaging agents activate a CrmA-insensitive apoptotic pathway involving CPP32 and that these signals differ from those associated with apoptosis induced by the Fas receptor.     

Identification and characterization of a low-affinity granulocyte- macrophage colony-stimulating factor receptor on primary and cultured human melanoma cells

Hematopoietic growth factor receptors are present on cells of normal nonhematopoietic tissues such as endothelium and placenta. We previously demonstrated functional human granulocyte-macrophage colony- stimulating factor (GM-CSF) receptors on small cell carcinoma of the lung cell lines, and others have reported that certain solid tumor cell lines respond to GM-CSF in clonogenic assays. In the current study, we examine human melanoma cell lines and fresh specimens of melanoma to determine whether they have functional GM-CSF receptors. Scatchard analyses of 125I-GM-CSF equilibrium binding to melanoma cell lines showed a mean of 542 +/- 67 sites per cell with a kd of 0.72 +/- 0.14 nmol/L. Cross-linking studies in the melanoma cell line, M14, showed a major GM-CSF receptor species of 84,000 daltons. Under the conditions tested, the M14 cells did not have a proliferative response to GM-CSF in vitro, nor was any induction of primary response genes detected by Northern analysis in response to GM-CSF. Studies to determine internal translocation of the receptor-ligand complex indicated less than 10% of the 125I-GM-CSF internalized was specifically bound to receptors. Primary melanoma cells from five surgical specimens had GM-CSF receptors; Scatchard analysis was performed on one sample, showing 555 sites/cell with a kd of 0.23 nmol/L. These results indicate that human tumor cells may express a low-affinity GM-CSF receptor protein that localizes to the cell surface and binds ligand, but lacks functional components or accessory factors needed to transduce a signal.