Front propagation in channels with spatially modulated cross section.

Propagation of traveling fronts in a three-dimensional channel with spatially varying cross section is reduced to an equivalent one-dimensional reaction-diffusion-advection equation with boundary-induced advection term. Treating the advection term as a weak perturbation, an equation of motion for the front position is derived. We analyze channels whose cross sections vary periodically with L along the propagation direction of the front. Taking the Schlögl model as a representative example, we calculate analytically the nonlinear dependence of the front velocity on the ratio L/l where l denotes the intrinsic front width. In agreement with finite-element simulations of the three-dimensional reaction-diffusion dynamics, our theoretical results predicts boundary-induced propagation failure for a finite range of L/l values. In particular, the existence of the upper bound of L/l can be completely understood based on the linear eikonal equation. Last, we demonstrate that the front velocity is determined by the suppressed diffusivity of the reactants for L≪l.

Stabilization of a scroll ring by a cylindrical Neumann boundary.

We study the interaction of phase singularities with homogeneous Neumann boundaries in one, two, and three spatial dimensions for the complex Ginzburg-Landau equation. The existence of a boundary-induced drift attractor, well known for spiral waves in two spatial dimensions, is demonstrated for scroll waves in three spatial dimensions. We find that a cylindrical Neumann boundary can lock a scroll ring, thus preventing the collapse of its closed filament.

Serum neuron-specific enolase (S-NSE) and the prognosis in small-cell lung cancer (SCLC): a combined multivariable analysis on data from nine centres.

The influence of pretreatment serum neuron-specific enolase (S-NSE) in addition to more conventional prognostic factors on survival duration in small-cell lung cancer (SCLC) was investigated in 770 patients from nine centres in six countries. The other variables included stage of disease, performance status (PS), age, sex, serum lactate dehydrogenase (S-LDH), serum alkaline phosphatase (S-AP), and serum carcinoembryonic antigen (S-CEA). Increased values of S-NSE (> 12.5 micrograms-1 l) were observed in 81% of the patients, whereas S-LDH, S-AP and S-CEA were elevated in only half of the patients or less. Multivariable analysis by Cox's proportional hazard model disclosed S-NSE as the most powerful prognostic factor followed by poor PS and extensive stage disease. If PS was ignored, S-LDH came up as a significant prognostic factor. S-AP, S-CEA, age and sex had no significant influence on the prognosis. The three prognostic factors, S-NSE, PS and stage of disease, enabled establishment of a prognostic index (PI) based on a simple algorithm PI = zNSE + z(stage) + 2zPS. This segregated the patients into four groups with clearly different prognosis. The median survival and 95% confidence intervals of the four groups were: 468 days (540-408), 362 days (405-328), 256 days (270-241) and 125 days (179-58). Based on the present results we recommend S-NSE and PS, in addition to stage, for prognostic stratification in treatment trials on SCLC.

Serum neuron specific enolase (S-NSE) reference interval evaluation by time-resolved immunofluorometry compared with a radioimmunoassay.

The serum neuron specific enolase (S-NSE; EC 4.2.1.11) reference interval was evaluated by DELFIA (Wallac) in 161 healthy blood donors and the method compared with the S-NSE RIA assay (Pharmacia). The DELFIA assay total analytical variation coefficient (CV%) was between 3.7% and 6.6%., the RIA CV% 7.6% to 13.1%. Late centrifugation (after hours) increased the variation as a result of contamination with blood cells. Log transformation into a gaussian distribution was selected by Box-Cox analysis and tested by two models: the gauss-distribution and the Refval transformation. The 95% reference intervals and corresponding 90% confidence intervals were: female 2.9-9.6 micrograms/l (2.6-3.2 and 8.5-10.7) micrograms/l and male 3.4-11.7 micrograms/l (3.0-3.8 and 10.2-13.2 micrograms/l). Mean values were significantly different (P < 0.001), female 5.3 (4.9-5.6), male 6.3 (5.8-6.7) micrograms/l. The serum NSE levels were analysed with both methods in a population of 110 patients. The results were significantly correlated (coefficient, 0.9896; r, 0.99; P < 0.0001-two tailed). For high S-NSE values (> 150.0 micrograms/l) differences between the methods exceeded the mean difference + 2S.D., while low concentrations were interconvertible. Maximal diagnostic efficacy was 0.91 for both assays, in DELFIA 17.2-23.9 micrograms/l and for RIA 17.2-21.9 micrograms/l. Identical sensitivity, specificity, discriminative power score, and likelihood ratio were found. The two methods are consequently interconvertible.

Treatment costs of adjuvant cytotoxic therapy in premenopausal breast cancer patients.

The interest in cost calculations of medical treatment programs has increased during the last decade. In the Danish Breast Cancer Cooperative Group's (DBCG) protocol 77B, 1,028 premenopausal patients were randomized after mastectomy to radiotherapy (RT) alone (control), RT + 12 cycles of cyclophosphamide (C) or to RT + 12 cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). This study analyzes the costs associated with systemic treatment and follow-up programs in the 3 regimens. Costs connected with the primary mastectomy and the radiotherapy, which were identical in the 3 regimens, have not been included in the analysis. The analysis shows that the expenses for the postoperative treatment and follow-up program for 9 years in the control regimen are 8,250 DKK, whereas the costs for the C regimen are 11,000 DKK, and the costs for the CMF regimen are 18,000 DKK.

A phase III trial comparing prednimustine (LEO 1031) to chlorambucil plus prednisolone in advanced breast cancer.

Prednimustine is an ester of chlorambucil and prednisolone. The drug has had some activity in experimental as well as in human tumors, including breast cancer. The objective of the current study is to compare the clinical effectiveness and toxicity of prednimustine with its components of chlorambucil plus prednisolone, and to compare the clinical effectiveness and toxicity of a continuous treatment with an intermittent one. Two hundred and one patients with advanced breast cancer were randomized to the following treatments: I: prednimustine continuously; 40 mg/m2 d; II: prednimustine intermittently, 160 mg/m2 d 1 to 5, repeated every three weeks; and III: chlorambucil 8 mg/m2 d plus prednisolone 8 mg/m2 d, both given continuously. All treatments were given orally. One hundred and ninety five patients were evaluable for assessment of response to the treatments. The response rates were 21% in both of the prednimustine-treated groups, whereas only 11% of the patients treated with chlorambucil and prednisolone responded. The duration of remission with continuous prednimustine was longer than with the other two treatment groups, but not significantly so. One hundred and ninety five patients were evaluable for assessment of hematologic toxicity. No differences were observed between the two prednimustine-treated groups, whereas the group treated with chlorambucil plus prednisolone experienced a significantly higher degree of leukopenia and/or thrombopenia. Subjective toxicities, nausea, vomiting and psychical symptoms were only moderate in the three treatment groups, but significantly more pronounced in the group treated with intermittent prednimustine. Because of these promising results, prednimustine should be compared to other alkylating agents in patients with advanced breast cancer in randomized trials.

The prognostic significance of weight loss and its integration in stage-grouping of oesophageal cancer.

166 patients suffering from oesophageal cancer were subdivided into two groups with respect to weight loss. Survival of patients with less than or equal to 10% weight loss was significantly longer than in patients with greater 10% weight loss. Within the group with less than or equal 10% weight loss, patients in initial poor physical condition who improved on parenteral nutrition did as well as those in a spontaneously good condition. 159 could be stage-grouped according to the UICC classification. This classification did not give a clear-cut stratification with respect to survival. If the patients were reclassified into three stages in a system combining UICC stages with degree of weight loss, significant differences in survival between the individual stages could be obtained. It is recommended that the degree of weight loss is integrated in the stage-grouping of oesophageal cancer.

Pharmacokinetics of medroxyprogesterone acetate administered by oral and intramuscular route.

The present study was undertaken to elucidate: 1) The relationship between plasma concentration of medroxyprogesterone-acetate (MPA, ClinovirR, Depo Provera, Upjohn) administered both orally and intramuscularly. 2) The relation between dose and plasma concentration of MPA. Nineteen patients entered the study. In each patient the plasma concentration was monitored after the administration of a single oral and one intramuscular dose of MPA at the following dosage levels: 100 mg (5 patients), 400 mg (5 patients), 800 mg (5 patients) and 1 200 mg (4 patients). The interval between the oral and i.m. administration was 1 week. The results show: 1) A very large interindividual variation in plasma concentration. 2) An increase in plasma concentration after both oral i.m. dose. 3) After the i.m. administration, plasma levels remained steady or increased slightly throughout the test period. 4) After the oral administration the concentration increased rapidly to reach a peak by 2-7 hours, subsequently decreasing. Peak concentrations were 2-10 times higher than after i.m. administration. 5) Over the test period, the plasma concentration x time (0-168 h) is similar in the two modes of administration.

Treatment of advanced breast cancer with progestins.

This paper reviews the theoretical background for the use of progestins in advanced breast cancer and the clinical experience obtained from 13 major studies. The average rate of response is about 30%, with somewhat higher rates when the dominant site of disease is localized to soft tissue and to bones, compared with viscera. Furthermore it seems that cross resistance between progestin therapy and other endocrine therapies is only partial. However, response rates related to previous therapy and to important prognostic variables such as age of the patient, disease-free interval and hormone receptor content of the tumor tissue are poorly elucidated. Only limited data are available concerning response rate in relation to dose and route of administration and data from prospective randomized trials to analyze these relations are still lacking. Considering the only modest side effects of treatment with progestins and the clinical and theoretical evidence favoring a mode of action different from that of other endocrine therapies, progestins are drugs with interesting qualities. Therefore future controlled studies with progestins alone or in combination with other systemic therapies should be carried out to establish the therapeutic efficacy of progestin therapy in primary and advanced disease.

Therapeutic effect of tamoxifen related to estrogen receptor level.

Cytoplasmic oestrogen receptor (ER) determinations were performed in 59 postmenopausal patients with metastatic breast cancer. Fifty percent of the patients were found to be ER+. Forty patients were treated with tamoxifen (TAM) and 19 patients were treated with tamoxifen plus medroxyprogesterone acetate (MPA). The response rate of TAM-treated patients was 30% (12/40). Of the 21 ER+ patients, ten (48%) responded to therapy. The ER values of these patients were significantly higher than the ER values of nonresponders (P less than 0.01). No correlation could be found between the ER value and the duration of remission in TAM-treated patients.

PIP: In this study of 59 postmenopausal patients with metastatic breast cancer, the therapeutic effect of tamoxifen (TAM) and/or TAM plus medroxyprogesterone acetate (MPA) was investigated and its effectiveness was related to the patients estrogen receptor (ER) levels. 3 studies are discussed: 1) Study 1, in which TAM was used alone; 2) Study 2, in which TAM was tested against TAM+MPA; and 3) Study 3, in which TAM was tested against TAM+diethylstilbestrol (DES). In this unselected population of post menopausal patients with metastatic breast cancer, the overall response rate to TAM treatment was 80% (12/40). Of 21 ER positive patients, 10 (48%) responded to TAM therapy. The ER values of these patients were significantly higher than the ER values of nonresponders (P .001), but no correlation was found between the ER value and the duration of remission in TAM-treated patients. These results are from the population of Studies 1 and 2; Study 3's population was too small for significant findings to be reported.