Preoperative serum levels of follicle stimulating hormone (FSH) and prognosis in invasive breast cancer.

AIMS: We investigated the association between preoperative serum levels of follicle stimulating hormone (FSH) and the prognosis in women with invasive breast cancer. METHODS: Serum levels of FSH were measured in 182 premenopausal and 581 peri- or postmenopausal women with invasive breast cancer. They were followed for a mean time of 84 months. The study endpoint was death from breast cancer (182 events). Analyses were stratified on menopausal status. RESULTS: None of the estimates showed a statistically significant result. In both pre- and postmenopausal women there was a nominally higher probability of survival with a higher FSH level. Point estimates in multivariate analysis incorporating age, tumour diameter, axillary lymph status, estrogen and progesterone receptor content and year of treatment indicated a stronger association with FSH levels in premenopausal than postmenopausal women (relative hazard 0.63 or 0.85, respectively in the highest compared with the lowest quartile). CONCLUSION: We did not find any statistically significant association between preoperative serum level of FSH and prognosis. Today, FSH is not a clinical target for intervention or a clinically useful prognostic factor and the results of clinical studies up to date can only be used for motivation of further experimental laboratory research.

Physicochemical characterisation of a drug-containing phospholipid-stabilised o/w emulsion for intravenous administration.

Clomethiazole (CMZ) was used as a model drug to be incorporated into an emulsion vehicle. The effects of drug concentration and number of homogenisation steps were evaluated using multiple linear regression. The droplet size, measured as a z-average diameter by photon correlation spectroscopy (PCS), was found to be between 60 and 260 nm in the investigated range of CMZ concentrations, highly dependent on the concentration, but more weakly so on the number of homogenisation steps. Slow-scanning high-sensitivity differential scanning calorimetry (DSC) measurements showed that CMZ depresses the phospholipid chain melting temperature in the emulsion system, whereas (13)C nuclear magnetic resonance (NMR) experiments suggested that the CMZ molecules are to a large extent located in the surface region of the emulsion droplets. This interpretation is compatible with results from NMR self-diffusion measurements, which showed that most of the CMZ molecules are rapidly exchanged between emulsion droplets and the aqueous surrounding. It can be concluded that the surface-active drug CMZ has a significant influence on the characteristics of phospholipid-stabilised emulsions through its ability to interact with the phospholipid interface. Thus, the results underline the importance of characterising drug-lipid interactions for the development of lipid-based formulations.

Pre-operative oestradiol levels - relation to survival in breast cancer.

AIMS: There are clinical observations that operation during the luteal phase of the menstrual cycle (with high oestradiol levels) may positively influence prognosis in breast cancer. However, few studies have information on plasma levels of hormones pre-operatively. METHODS: We studied 774 women treated for breast cancer where plasma levels of oestradiol had been measured 1-2 days pre-operatively. Date and cause of death were ascertained from the files of the Swedish Cancer Register and 5434 person-years were observed. The endpoint was death with breast cancer as the underlying cause (n=41 and n=158 in the pre- and post-menopausal group, respectively). RESULTS: In life-table analyses, only pre-menopausal patients with oestradiol 500 pmol/l and above had a tendency (not statistically significant) for better survival. Multivariate Cox models with oestradiol modelled in continuous form yielded relative hazards (RH) close to unity in all women and in strata according to menopausal status. CONCLUSIONS: When oestradiol was analysed in categorized form, only women with the highest levels had a tendency for improved prognosis (RH around 0.7; not statistically significant). Moreover, this pattern was not apparent for pre-menopausal women. Our findings contradict the notion that the pre-operative oestradiol level is independently associated with breast cancer prognosis.

Cubic phases for studies of drug partition into lipid bilayers.

Drug partition into lipid bilayers in a cubic liquid-crystalline phase was investigated. Glyceryl monooleate was used to form the lipid bilayer in a reversed bicontinuous cubic liquid-crystalline phase. The reason for using the cubic phase is that it may coexist with an external aqueous phase, and that the phase boundary (cubic phase/aqueous bulk) is well-defined due to the stiffness of the cubic phase. This makes the cubic phase a potential candidate for high throughput screening (HTS) of the lipophilicity and the dissociation constant (if any) of drug compounds. Clomethiazole (CMZ), lidocaine, prilocaine and 4-phenylbutylamine (4-PBA) were chosen as model drug compounds. It was shown that it is possible to determine a pH-dependent apparent partition coefficient, Kbl/w, of a drug compound using a lipid bilayer expressed as a cubic liquid-crystalline structure. Good agreement was found when the resulting Kbl/w vs. pH curves for CMZ, lidocaine and prilocaine were fitted to a mathematical expression. This included the bilayer/water partition coefficient for the unionised and ionised drug respectively and the pKa of the drug. The effect of different experimental conditions; such as amount of cubic phase, temperature, agitation, sample preparation and interfacial area between the cubic phase and the aqueous bulk on the partition kinetics were investigated as well. The studies reveal that the time needed to reach partition equilibrium was, as expected, substantially reduced (from days to hours) by decreasing the amount of cubic phase, increasing the interfacial area between the cubic phase and the aqueous phase, and increasing the temperature and the agitation of the sample. It was also shown that the bilayer affinity of 4-PBA was increased when a zwitterionic lipid (i.e. dioleoyl phosphatidylcholine, DOPC) was incorporated in the bilayer.

Mammographic screening for breast cancer. What cancers do we find?

The aim of this study was to compare lymph node involvement of breast cancer cases detected at mammography screening with clinically-detected cases. During a 3-year period, 273 primary breast cancers were detected in a population-based screening programme, and 149 primary breast cancers were diagnosed clinically. Lymph node involvement was evaluated in univariate and multivariate logistic regression models correcting for tumour size, histological grade, steroid receptor status and DNA-ploidy. Patients with screen-detected cancers had a low relative risk of having lymph node metastases (univariate, OR = 0.31; 95% confidence interval = 0.19-0.52). In the multivariate logistic regression model, the relative risk was halved (OR = 0.47; 0.28-0.78). The reduced risk was more pronounced for women younger than 50 years of age compared to older women. The risk for screen-detected cases of having lymph node metastases at diagnosis was statistically significantly lower than for clinically-detected cases. The marked reduction, even when correcting for tumour size, makes it less likely that factors such as detection of clinically innocent tumours, length bias sampling or clinical symptoms related to axillary metastases can explain the whole difference. The results indicate at least part of the effect may be explained by tumour progression in the late preclinical detectable phase.

Prognostic characteristics in breast cancers after hormone replacement therapy.

We examined the influence of hormone replacement therapy (HRT) on breast tumour biology by comparing the prognostic characteristics of breast cancers and survival in 121 women prescribed replacement hormones before diagnosis with those in 1468 women without such treatment. The women receiving HRT had a lowered relative risk of being diagnosed with tumours of more than 20 mm in diameter, OR = 0.7 (CI 0.5-1.0) and axillary lymph node dissemination, OR = 0.7 (CI 0.4-1.1). These risk reductions were most pronounced and statistically significant in the women who had been prescribed a combined estradiol-progestin regimen. The patients in this compound group also had a diminished relative risk of having poorly differentiated tumours. Further, there was an indication that the women prescribed HRT, and especially those with conjugated estrogens/estradiols alone, had a decreased relative risk of developing aneuploid tumours. There was no clear pattern for women receiving the biologically weak oestriol, although risk estimates were generally higher for unfavourable tumours in comparison with those receiving the higher potency compounds. Adjustments for indications of earlier detection (i.e. lead time bias) did not influence the pattern or magnitude of the risk estimates. No association between any type of HRT and survival after breast cancer diagnosis was noted, but analyses were based only on 19 breast cancer deaths among exposed patients. We conclude that breast cancers occurring after treatment with HRT, especially the combined estrogen-progestin regimen, seem to have more favourable tumour features than tumours in non-treated women. Our findings may reflect a less aggressive biological behaviour of breast cancers in women receiving HRT, or in part be explained by the earlier detection of the tumours in these women.

Defining a high mortality risk group among women with primary breast cancer.

Increasing interest has been focused on DNA ploidy, hormone receptor status and tumour size as prognostic factors in node-negative breast cancer. We analysed these factors in patients operated on for primary invasive breast cancer between January 1981 and December 1987 in a prospective study of 248 women with no involved axillary nodes and 188 women with positive nodes followed until 15 April 1989. Oestrogen or progesterone receptor negativity, aneuploidy and tumour diameter exceeding 20 mm were studied as negative prognostic signs in life table analyses and Cox proportional hazards models of corrected survival. Corrected survival decreased with increasing number of negative signs. Three to four signs yielded a statistically significant, two- to threefold higher risk than the others. Survival estimates by life table analyses differed by 20% at 5 years. In the whole group, women with three or four negative factors had a relative risk of dying from their disease more than twice that of the others. Women with no involved nodes and with three or four negative factors had a risk of dying from breast cancer similar to that of node-positive women with fewer than three.

A long-term cross-over pharmacokinetic study comparing perphenazine decanoate and haloperidol decanoate in schizophrenic patients.

The purpose of the study was to investigate clinical and pharmacokinetic parameters concerning perphenazine decanoate (PD) and haloperidol decanoate (HD) with an interval of 3 weeks during a study period of 51 weeks. This was done by using the available drug preparations in chronic schizophrenic patients in a randomised, double-blind, cross-over, multicentre study. In addition, an elimination phase of 6 weeks was added, when no IM injections of the depot drugs were given. Twenty-nine patients in a stable neuroleptic maintenance phase entered the study. The patients were rated during the trial according to the CPRS-SCHZ and CGI scales, the UKU side effect scale and serum concentrations of the drugs and prolactin were monitored. There was no significant difference between the drugs in antipsychotic efficacy or side effects. Thus, the doses were equipotent with regard to the CPRS-SCHZ scores. However, the patients' global improvement rating was higher for PD (52%) than for HD (39%) (P > 0.05). The elimination of both drugs was very slow. No interaction effects between PD and HD were observed. The serum levels of HD were in most patients lower than those recommended for acute-subacute treatment. The mean doses were 117 mg (0.29 mmol), range 20-313 mg PD and 120 mg (0.32 mmol), range 20-350 mg HD. The serum concentrations in nmol/L of perphenazine and haloperidol (week 24) were 0.8-15.9 and 2.3-46.7, respectively.

Age as a determinant of axillary node involvement in invasive breast cancer.

We analyzed the age at diagnosis and the tumor size as determinants of axillary node involvement in 725 consecutive patients with breast cancer. The prevalence of nodal involvement increased consistently with tumor diameter from 18.9% in tumors smaller than 10 mm to 72.9% in those measuring 40 mm, or more. The risk also varied with age, the lowest prevalence being found in the youngest and the oldest patients and the highest one in the 40-59-year age group. When analyzed as a continuous variable age was best fitted as a second order term and it was a statistically significant (p = 0.04) determinant of axillary metastases in a multivariate model where tumor diameter, histopathological classification and estrogen receptor concentration were taken into account as possible confounding variables. The findings indicate that the parallelism between the establishment of metastases in lymph nodes and at distant sites may vary with age. The prognostic value of nodal status may therefore depend on age at diagnosis.