Persistent induction of nitric oxide synthase in tumours from mice treated with the anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid.

An anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA) induced nitric oxide synthase (NOS) in the tumour, spleen, thymus and small intestine, but not in the lung, liver, kidney, heart or skeletal muscle in B6D2F1 mice bearing subcutaneous colon 38 tumours. This pattern of induction is distinct from that caused by agents such as endotoxin, muramyl dipeptide or Corynebacterium parvum. The induction of NOS (iNOS) in the tumour was more persistent (maximal at 3 days) than in other tissues (maximal at 12 h). Immunohistochemical staining suggested that iNOS was located in macrophages and endothelial cells within and around the tumour. Treatment with 5,6-MeXAA also caused substantial increases in plasma nitrite and nitrate (NOx) concentrations that peaked at 8-12 h after 5,6-MeXAA. The increase in plasma NOx was prevented by a NOS inhibitor N-iminoethyl-L-ornithine (L-NIO), indicating that it was due to enhanced production of NO. Tumour-bearing mice were more responsive than controls to 5,6-MeXAA both in their plasma NOx increase and in their lower maximally tolerated dose. L-NIO was unable to prevent the complete tumour necrosis and regression caused by 5,6-MeXAA at a dose that substantially inhibited the increase of plasma NOx. In conclusion, the experimental anti-tumour agent 5,6-MeXAA induced NO synthesis in tumour-associated macrophages and in immunologically active tissues in parallel with its effects on tumour growth. The experiments with a non-selective NOS inhibitor L-NIO, however, suggest that NO is not a significant component in the mechanism of the anti-tumour action of 5,6-MeXAA in this particular model.     

Effect of the viable-yellow (A(vy)) agouti allele on skin tumorigenesis and humoral hypercalcemia in v-Ha-ras transgenic TGxAC mice

We previously reported that papillomas can arise from the follicular epithelium of v-Ha-ras transgenic TGxAC mice. Since the viable-yellow mutation (A(vy)) of the mouse agouti gene which regulates coat color pigmentation by acting within the micro-environment of the hair follicle has been shown to function as a tumor promoter in the liver, we hypothesized that it may also play a role in TGxAC skin tumorigenesis. Endogenous agouti protein product was detected in the outer root sheath of anagen hair follicles following plucking of the hair shaft, but not in the interfollicular epithelium, in TGxAC mice on an FVB/N genetic background. It was also detected in papillomas from these mice produced by 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment or plucking. Expression of the A(vy) allele in the v-Ha-ras transgenic TGxAC mouse line results in an approximately 2-fold increase in papilloma development compared with controls which did not carry the A(vy) allele following twice-weekly treatment with 1.25, 2.5 or 5.0 microg TPA. In addition, TPA-treated, papilloma-bearing F1 mice which carried the A(vy) allele, but not F1 mice which did not carry the A(vy) allele, exhibited a syndrome of humoral hypercalcemia mediated by parathyroid hormone-related protein (PTHrP) that led to weight loss, hypercalcemia and hypophosphatemia. Thus, we conclude that the A(vy) allele can influence the development of skin tumors and PTHrP-mediated humoral hypercalcemia in v-Ha-ras transgenic TGxAC mice.      

Teniposide or carboplatin in patients with recurrent or advanced cervical carcinoma: A randomized phase II trial

Thomsen TK, Pfeiffer P, Bertelsen K. Teniposide or carboplatin in patients with recurrent or advanced cervical carcinoma: A randomized phase II trial. Int J Gynecol Cancer 1998; 8 : 310–314.
The aim of the present study was to investigate response rates, time to progression, and survival with teniposide or carboplatin in patients with advanced or recurrent cervical cancer and to estimate the toxicity of each drug regimen.
Twenty-eight patients with recurrent or advanced cervical cancer entered the study. Two patients were ineligible (severe renal impairment, n = 1; performance status 3, n = 1) and were excluded from the analysis. The remaining 26 patients were randomized to either carboplatin (400 mg/m² on day 1, intravenously every four weeks) or teniposide (125 mg/m² on days 1, 2 and 3, intravenously every four weeks). Twelve patients were randomized to the carboplatin arm and 14 patients to the teniposide arm. They were all comparable with respect to age, performance status, histology, primary FIGO stage, and prior therapy.
Response was seen in four patients in each group (33% and 29%, respectively), all but one being partial. (One patient in the teniposide group had complete response). Time to progression and median survival were similar in the two groups (median time to progression 20/17 weeks and median survival 40/41 weeks, respectively.)
In general, toxicity was moderate. Leukopenia (WHO grade 3 or 4) was seen in one patient treated with teniposide, and thrombocytopenia (WHO grade 3 or 4) in one patient treated with carboplatin. Eleven patients (79%) in the teniposide group had alopecia requiring a wig. The study implies that both drugs have some activity in cervical cancer. Carboplatin has the advantage that it can be administered on an out-patient basis.     

Gestational age, birth weight, and the risk of hyperkinetic disorder.

AIMS: To study the association between gestational age and birth weight and the risk of clinically verified hyperkinetic disorder. METHODS: Nested case-control study of 834 cases and 20 100 controls with incidence density sampling. RESULTS: Compared with children born at term, children born with gestational ages of 34-36 completed weeks had a 70% increased risk of hyperkinetic disorder (rate ratio (RR) 1.7, 95% confidence interval (CI) 1.2 to 2.5). Children with gestational ages below 34 completed weeks had an almost threefold increased risk (RR 2.7, 95% CI 1.8 to 4.1). Children born at term with birth weights of 1500-2499 g had a 90% increased risk of hyperkinetic disorder (RR 1.9, 95% CI 1.2 to 2.9), and children with birth weights of 2500-2999 g had a 50% increased risk (RR 1.5, 95% CI 1.2 to 1.8) compared with children born at term with birth weights above 2999 g. The results were adjusted for socioeconomic status of the parents, family history of psychiatric disorders, conduct disorders, comorbidity, and maternal smoking during pregnancy. Results related to birth weight were unchanged after adjusting for differences in gestational age. CONCLUSIONS: Children born preterm, also close to term, and children born at term with low birth weights (1500-2499 g) have an increased risk of clinically verified hyperkinetic disorder. These findings have important public health perspectives because the majority of preterm babies are born close to term.     

Increased fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) uptake in childhood CNS tumors is correlated with malignancy grade: a study with FDG positron emission tomography/magnetic resonance imaging coregistration and image fusion.

PURPOSE Positron emission tomography (PET) has been used in grading of CNS tumors in adults, whereas studies of children have been limited. PATIENTS AND METHODS Nineteen boys and 19 girls (median age, 8 years) with primary CNS tumors were studied prospectively by fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) PET with (n = 16) or without (n = 22) H(2)(15)O-PET before therapy. Image processing included coregistration to magnetic resonance imaging (MRI) in all patients. The FDG uptake in tumors was semiquantitatively calculated by a region-of-interest-based tumor hotspot/brain index. Eight tumors without histologic confirmation were classified as WHO grade 1 based on location, MRI, and clinical course (22 to 42 months). Results Four grade 4 tumors had a mean index of 4.27 +/- 0.5, four grade 3 tumors had a mean index of 2.47 +/- 1.07, 10 grade 2 tumors had a mean index of 1.34 +/- 0.73, and eight of 12 grade 1 tumors had a mean index of -0.31 +/- 0.59. Eight patients with no histologic confirmation had a mean index of 1.04. For these 34 tumors, FDG uptake was positively correlated with malignancy grading (n = 34; r = 0.72; P < .01), as for the 26 histologically classified tumors (n = 26; r = 0.89; P < .01). The choroid plexus papilloma (n = 1) and the pilocytic astrocytomas (n = 3) had a mean index of 3.26 (n = 38; r = 0.57; P < .01). H(2)(15)O-uptake showed no correlation with malignancy. Digitally performed PET/MRI coregistration increased information on tumor characterization in 90% of cases. CONCLUSION FDG PET of the brain with MRI coregistration can be used to obtain a more specific diagnosis with respect to malignancy grading. Improved PET/MRI imaging of the benign hypermetabolic tumors is needed to optimize clinical use.     

Value of 8S/4S fractionation of estrogen receptors (ER) for prediction of response to hormonal manipulation in metastatic breast cancer

Summary Using sucrose gradient centrifugation, human breast cancer estrogen receptors appear in two molecular forms sedimenting at either 8S or 4S fractions. The sum of these two fractions has been valuable clinically in helping to predict response to hormonal therapies. It has been suggested that the 4S receptor may not be of predictive value and that the practice of using only dextran-coated charcoal methodology might thus overestimate the number of patients whose tumors might be hormonally dependent. The present study correlates clinical response to hormonal manipulations with 8S and 4S receptors as determined by sucrose density gradient centrifugation. Patients with only 4S positive receptors had a 56% response rate to hormonal manipulation compared with a 52% response rate in patients with positive 8S alone or with both 8S and 4S receptors. Although patient numbers are small in this and the other three published series addressing this question, our data do not confirm two previously published studies suggesting clinical importance of 8S/4S fractionation.