No abstract

is an immunostimulatory cytokine with antitumor activity in preclinical animal models. A phase I study of recombinant human IL-18 (rhIL-18) was done to determine the toxicity, pharmacokinetics, and biological activities of rhIL-18 in patients with advanced cancer. Experimental Design: Cohorts of patients were given escalating doses of rhIL-18, each administered as a 2-hour i.v. infusion on 5 consecutive days. Toxicities were graded using standard criteria. Serial blood samples were obtained for pharmacokinetic and pharmacodynamic measurements. Results: Twenty-eight patients (21with renal cell cancer, 6 with melanoma, and 1with Hodgkin's lymphoma) were given rhIL-18 in doses ranging from 3 to 1,000 Ag/kg. Common side effects included chills, fever, nausea, headache, and hypotension. Common laboratory abnormalities included transient, asymptomatic grade 1to 2 neutropenia, thrombocytopenia, anemia, hypoalbuminemia, hyponatremia, and elevations in liver transaminases. One patient in the100 Ag/kg cohort experienced transient grade 3 hypotension and grade 2 bradycardia during the first infusion of rhIL-18. No other dose-limiting toxicities were observed. Plasma concentrations of rhIL-18 increased with increasing dose, and 2.5-fold accumulation was observed with repeated dosing. Biological effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens onlymphocytes and monocytes. Increases in serum concentrations of IFN-g, granulocyte macrophage colony-stimulating factor, IL-18 bindingprotein, and soluble Fasligand were observed. Two patients experiencedunconfirmed partial responses after rhIL-18 treatment. Conclusions: rhIL-18 can be safely given in biologically active doses to patients with advanced cancer. A maximum tolerated dose of rhIL-18 was not determined. Further clinical studies of rhIL-18 are warranted. Interleukin (IL)-18 is an immunostimulatory cytokine thatregulates both innate and adaptive immune responses (1, 2). The effects of IL-18 are mediated through a specific cell surface receptor complex composed of at least two subunits, an a chain (IL-1Rrp1) and a h chain (AcPL; ref. IL-18 has antitumor activity in animal models (8 -12). Regression of tumors in IL-18-treated animals is not dependent on the presence of IFN-g or IL-12 but seems to require an intact Fas/Fas ligand pathway (9, 10). The antitumor effects of IL-18 in multiple animal models provided the rationale for investigation of recombinant human (rh) IL-18 in cancer immunotherapy. We describe the results of the first clinical trial of rhIL-18 in patients with cancer. Materials and MethodsPatient selection. Eligible patients included adults (ages >18 years) with histologically confirmed, locally advanced, or metastatic solid tumor or lymphoma that was measurable and refractory to standard

Despite decades of intensive research, the development of a diagnostic test for major depressive disorder (MDD) had proven to be a formidable and elusive task, with all individual marker-based approaches yielding insufficient sensitivity and specificity for clinical use. In the present work, we examined the diagnostic performance of a multi-assay, serum-based test in two independent samples of patients with MDD. Serum levels of nine biomarkers (alpha1 antitrypsin, apolipoprotein CIII, brain-derived neurotrophic factor, cortisol, epidermal growth factor, myeloperoxidase, prolactin, resistin and soluble tumor necrosis factor alpha receptor type II) in peripheral blood were measured in two samples of MDD patients, and one of the non-depressed control subjects. Biomarkers measured were agreed upon a priori, and were selected on the basis of previous exploratory analyses in separate patient/control samples. Individual assay values were combined mathematically to yield an MDDScore. A 'positive' test, (consistent with the presence of MDD) was defined as an MDDScore of 50 or greater. For the Pilot Study, 36 MDD patients were recruited along with 43 non-depressed subjects. In this sample, the test demonstrated a sensitivity and specificity of 91.7% and 81.3%, respectively, in differentiating between the two groups. The Replication Study involved 34 MDD subjects, and yielded nearly identical sensitivity and specificity (91.1% and 81%, respectively). The results of the present study suggest that this test can differentiate MDD subjects from non-depressed controls with adequate sensitivity and specificity. Further research is needed to confirm the performance of the test across various age and ethnic groups, and in different clinical settings.

No abstract