This study of NK105 (150 mg PTX equivalent/m(2)) proves the concept for the modest activity and tolerability of a new drug delivery system formulation for PTX. A phase III trial will be evaluated to clarify survival benefit.

No abstract

Enhanced vascular permeability in tumor tissue has profound pathological consequences in tumor biology. However, details of the mechanism involved are not clear. The present work on tumor vascular permeability has led to the following three findings, (i) Ascitic tumor fluid contained kinin (about 1‐40 ng/ml), which is known to enhance vascular permeability and induce pain in vivo, (ii) Kinin is generated via the kallikrein‐dependent cascade in the ascitic tumor fluid. By blocking this kinin‐generating cascade with Kunitz‐type soybean trypsin inhibitor the formation of ascites was suppressed, (iii) Blocking of kinin‐degrading enzymes (kininases I and II) by an appropriate kininase inhibitor (e.g., captopril) may result in increased permeability, leading to accumulation of the ascitic fluid. This phenomenon was verified by an about 1.2‐1.5 fold increase in leakage of 51Cr‐labeled bovine serum albumin into the ascites when kininase inhibitors had been administered orally 30 min before intravenous administration of the bovine serum albumin.

The role of the bradykinin‐generating system in the pathogenesis of cancer was explored by simultaneously measuring plasma prekallikrein (PK), the precursor of kallikrein, which is the major enzyme responsible for kinin generation, and plasma kininogens (KNG), which are precursors of kinin, in patients with various cancers. The mean value of plasma PK in healthy volunteers was 2.5 ± 0.5 (mean ± SD) units/mg plasma protein and that in cancer patients (all stage IV) was 1.7 ± 0.7 units/ mg plasma protein. The mean value of plasma KNG in healthy volunteers was 12.5 ± 2.0 ng kinin equivalents/mg plasma protein and that in cancer patients was 10.9 ± 2,8 ng. These data showed that plasma PK and plasma KNG values were significantly lower in cancer patients compared with healthy volunteers (P < 0.0005 for PK; 0.0005 < P < 0.005 for KNG; n = 28 for healthy subjects; n = 29 for cancer patients). These data appear to indicate that conversion of PK to kallikrein would probably occur with concomitant consumption of KNG by newly generated kallikrein for kinin generation in cancer patients. Early stage cancer patients showed little difference from healthy volunteers. For the in vitro study, activation of purified Hageman factor (HP) and PK was examined by using cancer cell lines and virus‐transformed cells that produced plasminogen activator (PA) at a high rate. Both HF and PK were activated in the presence of plasminogen. Diploid cell lines and primary fibroblasts, which did not produce PA, activated neither HF nor PK. Taking all these data together, we conclude that kinin generation does occur in the plasma of patients with advanced cancer, and that one of the initiation mechanisms of the kinin‐generating cascade appears to be mediated by plasmin and to depend on cancer cell‐derived PA activity.

Objective-To evaluate secular trends in the incidence and prevalence of rheumatoid arthritis (RA) in Japan. Methods-The incidence and prevalence of RA were determined in a longitudinal population based study in the Kamitonda district, Wakayama, Japan, from 1965 to 1996. Results-In the study area consisting of about 3000 inhabitants, 16 incident cases, satisfying definite RA by the Rome criteria were detected during the study period. The age and sex adjusted incidence in both men and women combined and the age adjusted incidence in women significantly decreased (p<0.025 and p<0.01, respectively). The age and sex adjusted prevalence in all inhabitants tended to decrease (p<0.1), and the age adjusted prevalence in women significantly declined (p<0.025). In men, however, neither incidence nor prevalence showed significant change. Conclusions-The decline of incidence and prevalence of female RA may be reducible to some environmental changes preferentially occurring more obviously in Japanese women than in men. Because the use of oral contraceptives has been extremely low in Japan, the decline should be explained by other factors. (Ann Rheum Dis 1999;58:751-756)