PK and PD studies indicated that a dose of 160 U/m2 lowered plasma arginine from a resting level of approximately 130 micromol/L to less than 2 micromol/L for at least 7 days; nitric oxide levels also were lowered. There were no grade 3 or 4 toxicities directly attributable to the drug. Six of 24 phase I to II patients responded to treatment (five partial responses and one complete response; 25% response rate) and also had prolonged survival. CONCLUSION Elimination of all detectable plasma arginine in patients with metastatic melanoma was well tolerated and may be effective in the treatment of this cancer. Further testing of ADI-SS PEG 20,000 mw in a larger population of individuals with metastatic melanoma is warranted.

BackgroundSocio-economic inequalities in mortality are observed at the country level in both North America and Europe. The purpose of this work is to investigate the contribution of specific risk factors to social inequalities in cause-specific mortality using a large multi-country cohort of Europeans.MethodsA total of 3,456,689 person/years follow-up of the European Prospective Investigation into Cancer and Nutrition (EPIC) was analysed. Educational level of subjects coming from 9 European countries was recorded as proxy for socio-economic status (SES). Cox proportional hazard model's with a step-wise inclusion of explanatory variables were used to explore the association between SES and mortality; a Relative Index of Inequality (RII) was calculated as measure of relative inequality.ResultsTotal mortality among men with the highest education level is reduced by 43% compared to men with the lowest (HR 0.57, 95% C.I. 0.52–0.61); among women by 29% (HR 0.71, 95% C.I. 0.64–0.78). The risk reduction was attenuated by 7% in men and 3% in women by the introduction of smoking and to a lesser extent (2% in men and 3% in women) by introducing body mass index and additional explanatory variables (alcohol consumption, leisure physical activity, fruit and vegetable intake) (3% in men and 5% in women). Social inequalities were highly statistically significant for all causes of death examined in men. In women, social inequalities were less strong, but statistically significant for all causes of death except for cancer-related mortality and injuries.DiscussionIn this European study, substantial social inequalities in mortality among European men and women which cannot be fully explained away by accounting for known common risk factors for chronic diseases are reported.

To examine the role of sex steroid hormones in the development of autoimmune diseases, we studied five patients with Klinefelter's syndrome associated with autoimmune disease, three of whom had Sjögren's syndrome (SS) and two of whom had systemic lupus erythematosus (SLE). Serum testosterone (T) and LH levels, antinuclear antibodies (ANA) and rheumatoid factor (RF) titers, erythrocyte sedimentation rate (ESR), hemolytic complement (CH50) levels, and peripheral T lymphocyte subsets (OKT3+, OKT4+, and OKT8+) were measured before treatment, after 60 days of placebo treatment, and after 60 days of oral T undecanoate (TU) treatment. Before treatment and after placebo, with respect to normal men, the patients had lower serum T and higher LH levels, lower percentages and absolute values of OKT3+ (total T lymphocytes) and OKT8+ (suppressor/cytotoxic T lymphocytes) cells, and, consequently, an increased OKT4/OKT8 ratio. Hemolytic complement (CH50) in serum was below normal in the two patients with SLE, while it was normal in the patients with SS. The ESR was above normal in all patients, and all had high titers of ANA and RF. After TU therapy, serum T levels increased and LH levels decreased, but not to normal. OKT3+ and OKT8+ cells and the OKT4/OKT8 ratio became normal, and RF and ANA titers decreased. The CH50 level did not change in the SS patients, while it increased to normal in the two patients with SLE. The ESR decreased in all patients during therapy. Furthermore, after TU therapy, both the SS and SLE patients had a clinical remission of their autoimmune disease. Our results indicate a therapeutic effect of T on autoimmune diseases in patients with hypogonadism and Klinefelter's syndrome.