Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid

We report the results of an expanded trial of 5-fluorouracil (FUra) combined with high-dose folinic acid for treatment of patients with advanced colorectal or gastric adenocarcinoma. In each treatment course, the patients received both FUra (340-400 mg/m2/day by iv infusion over 15 minutes) and folinic acid (200 mg/m2/day by iv bolus) for 5 consecutive days, with a 21-day interval between courses. Eighty-six patients with colorectal carcinoma were evaluated. The combined complete response (CR) and partial response (PR) rates were 39% for 54 patients who did not receive prior chemotherapy and 22% for 32 patients who had previously received chemotherapy. Four patients who were previously resistant to FUra attained objective responses. The median time to disease progression for the 28 responders was 10 months. The median survival time of responders was 19.5 months, and the probability of their being alive at 2 years was 40%. Of 27 patients with gastric adenocarcinoma, 13 (48%) responded to therapy. Their median time to disease progression was 5.5 months. The median survival time of responders was 11 months, and their probability of being alive at 15 months was 30%. Toxicity was within acceptable limits. Toxic effects included stomatitis, diarrhea, conjunctivitis, skin rash, and mild myeloid hypoplasia. In a separate study, plasma concentrations of L-folates above 10(-5) M were achieved after a rapid single iv injection of 200 mg/m2 of folinic acid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Logistic multiple regression analysis of factors predicting recurrence of hyperthyroidism after medical treatment of toxic diffuse goitre.

In order to determine which factors predict the outcome of short term antithyroid drug treatment we studied 42 patients with diffuse goitre in whom 43 instances of thyrotoxicosis were treated. Treatment duration ranged from 24 to 61 wk (median 30 wk). All patients received high-dose carbimazole and thyroid hormone substitution. Patients in remission were followed for 39 to 134 wk (median 73 wk). The relapse rate at 1 yr and at 2 yr after cessation of antithyroid drug treatment was 51%. Of the parameters studied presence or absence of eye signs and initial serum levels of thyroxine, triiodothyronine and immunoglobulin-G in the relapse group and in the remission group showed significant differences in univariate analysis. No significant differences were found for age, sex, family history of thyroid disease, thyroid gland volume or TSH-receptor stimulating autoantibodies. Linear discriminant analysis shows that of the four remaining factors thyroxine is not important in separating both groups. Cox analysis yields only initial serum triiodothyronine and eye signs as significant prognostic factors. With these two factors 18 out of 23 predictions of remission and 16 out of 18 predictions of relapse in the 41 patients with known initial serum triiodothyronine concentrations are correct. Such predictions can be used in the choice of therapy, short-term medical treatment for patients with a low risk and long-term medical treatment or, at the appropriate time, a destructive form of therapy for patients with a high risk of relapse.     

Presence and measurement oftele-methylhistamine in mast cells

The histamine metabolitetele-methylhistamine (t-MH) was identified and measured in crude and purified peritoneal mast cells (MCs). Peritoneal dialysates, peritoneal cells, and purified MCs all containedt-MH in concentrations representing about 0.2% of the corresponding histamine (HA) levels.T-MH levels in crude cells represented about 70% of the total dialysate levels, indicating the presence of extracellular as well as intracellulart-MH.T-MH levels per MC in purified fractions were similar to those of crude fractions, indicating a MC origin for the intracellulart-MH. Histamine methyltransferase activity was not detected in crude or purified MC fractions, and incubations with the monoamine oxidase inhibitor pargyline failed to increase the content or release oft-MH in either fraction, suggesting a very slow or non-existent histamine methylation in MCs. Compound 48/80 produced a temperature-dependent release of HA andt-MH in crude and purified preparations, and Triton X-100 also released both amines. In all cases, the degree of release of both amines was correlated, consistent with a granular origin fort-MH in MCs. The low concentrations oft-MH in MCs do not necessarily indicate a role for MCs in HA metabolism, but suggest thatt-MH may be a valuable marker for non-MC HA.     

No evidence for involvement of the calpain-10 gene 'high-risk' haplotype combination for non-insulin-dependent diabetes mellitus in early onset obesity

In light of evidence of linkage of obesity to chromosome 2q31-q37, we hypothesized that the calpain-10 gene 'high-risk' haplotype combination for non-insulin-dependent diabetes mellitus (NIDDM) is involved in early onset obesity. We screened the NIDDM 'high-risk'-haplotype combination formed by the alleles 112 and 121 of the polymorphisms UCSNP-43, -19, and -63 in 166 families consisting of an extremely obese child or adolescent (mean BMI percentile: 99.3+/-1.38), one or more obese sibs (mean BMI percentile: 97.42+/-2.88), and both of their parents. Genotyping for three calpain-10 gene polymorphisms was performed by polymerase chain reaction (PCR) with (a) length polymorphism detection (UCSNP-19) or (b) allele-specific PCR (UCSNP-43 and -63). To allow for correct haplotype assignment all individuals were additionally genotyped for two microsatellite markers (D2S125 and D2S2338). We followed a hierarchical test procedure. As the first step, model-free linkage analysis was performed using maximum likelihood binomial statistics. The second stage consisted of a one-sided asymptotic pedigree disequilibrium test for the UCSNP-43 and on an exploratory level for the other SNP-markers and all haplotypes formed by the three SNPs. The final stage investigated the reported haplotype combination. We failed to detect an initial linkage of obesity to this region (LOD score <0.4). All subsequent exploratory analyses were negative. Our analysis of the relationship between the NIDDM 'high-risk' haplotype combination and extreme early onset obesity revealed no evidence for linkage and association.     

Two sibs with Wiedemann-Rautenstrauch syndrome: possibilities of prenatal diagnosis by ultrasound.

A girl with Wiedemann-Rautenstrauch syndrome was born to a non-consanguineous couple. During the pregnancy, growth retardation particularly in the biparietal and abdominal diameters but not the femoral length was detected through serial ultrasound scans. When the woman became pregnant again, in spite of having been assessed as having a 25% risk of recurrence, the prenatal findings seen in her previous pregnancy led us to suggest sequential echography and a similar pattern of growth retardation was shown. After termination, the male fetus was found to be affected by Wiedemann-Rautenstrauch syndrome. This case shows that ultrasound examination can be a useful tool in the prenatal diagnosis of this rare, autosomal recessive syndrome.     

Comparative study ofin vitro inhibition of activation of the classical and alternative pathways of human complement by the magnesium and sodium salts of the anti-inflammatory peptide N-acetyl-aspartyl-glutamic acid (NAAGA)

The inhibitory activity of the sodium salt of the anti-inflammatory peptide N-acetyl-aspartyl-glutamic acid (NAAGA) on activation of the classical and alternative pathways of human complement was compared with that of the clinically used magnesium salt of NAAGA (NAAGA-Mg). Sodium salt of NAAGA (NAAGA-Na) inhibited both pathways of activation in a dose-dependent manner at concentration ranging from 1 to 10 mM by acting on formation and/or function of the C3 convertases as shown by the inhibitory capacity of the peptide on the release of the C3 cleavage fragment C3b and C3a. NAAGA-Na was as effective as NAAGA-Mg in inhibiting classical pathway activation at concentration above 10 mM. NAAGA-Na was more effective than NAAGA-Mg in inhibiting the alternative pathway since the sodium salt did not interfere with Mg-dependent formation of the alternative pathway C3 convertase.     

Activated type II collagen reactive T cells are not eliminated by in vivo anti-CD4 treatment. Implications for therapeutic approaches on autoimmune arthritis.

Activation of CD4+ T cells plays an important role in type II collagen (CII) induced arthritis (CIA). The CD4+ T cell dependency is demonstrated by anti-CD4 antibody treatment which suppresses CIA in mice if injected before CII immunization. The same anti-CD4 treatment at a later stage does not suppress CIA, despite extensive elimination of peripheral CD4+ T cells. A possible explanation for this discrepancy is that activated T cells might not be as easily influenced by the anti-CD4 antibodies as resting T cells. To address this question, the proliferative capacity of CII reactive CD4+ lymph node (LN) T cells, in mice treated with anti-CD4 antibodies before or after the CII immunization, was analyzed. In mice treated before immunization the capacity of LN cells to proliferate in vitro was markedly suppressed while in mice receiving anti-CD4 treatment after immunization it was retained. Flow cytometric analysis revealed that the anti-CD4 treatment before and after immunization reduced the number of CD4+ LN T cells to the same level. The small population of CD4+ LN cells which were left after anti-CD4 treatment of naive mice all expressed CD44, a marker for previously activated T cells in mice. We propose that activation render CII reactive T cells more resistant to anti-CD4 treatment than virgin T cells are and suggest that the lack of therapeutic effect of late anti-CD4 treatment in CIA does not necessarily implicate that CD4+ T cells are unimportant in that stage of the disease.