Investigation of endometrial abnormalities in asymptomatic women treated with tamoxifen and an evaluation of the role of endometrial screening.

PURPOSE: Tamoxifen is the most commonly prescribed adjuvant therapy for women with breast cancer. It has agonist activity on the endometrium and is associated with an increased risk of endometrial cancer. The aim of this study was to evaluate whether screening with transvaginal ultrasound (TV USS) with or without hysteroscopy is worthwhile. PATIENTS AND METHODS: A total of 487 women with breast cancer, 357 treated with tamoxifen and 130 controls, were screened with TV USS, and endometrial thickness was measured. Women with thickened endometrium underwent outpatient hysteroscopy. RESULTS: Length of time on tamoxifen ranged from 5 to 191 months (mean, 66 months), and endometrial thickness ranged from 1 to 38 mm (mean, 7.3 mm). Women treated with tamoxifen had significantly thicker endometrium than did controls (P <.0001). There was a statistically significant (P <.0001) positive correlation between length of time on tamoxifen and endometrial thickness. One hundred forty-five women had endometrium greater than 5 mm on USS, and 134 underwent successful outpatient hysteroscopy, 61 of whom had atrophic endometrium, resulting in a 46% false-positive scan rate. The remaining women all had benign features to explain the USS findings. CONCLUSION: TV USS detects a high incidence (41%) of apparent endometrial thickening in women treated with tamoxifen, although 46% had atrophic endometrium on further assessment, and none of the remaining asymptomatic women had significant lesions. Length of time on tamoxifen relates to endometrial thickening as measured by TV USS. TV USS is a poor screening tool because of the high false-positive rate. The low frequency of significant findings suggests that endometrial screening in asymptomatic women is not worthwhile.

14 years of follow-up from the Edinburgh randomised trial of breast-cancer screening.

BACKGROUND: The Edinburgh randomised trial of breast-cancer screening recruited women aged 45-64 years from 1978 to 1981 (cohort 1), and those aged 45-49 years during 1982-85 (cohorts 2 and 3). Results based on 14 years of follow-up and 270,000 woman-years of observation are reported. METHODS: Breast-cancer mortality rates in the intervention group (28,628 women offered screening) were compared with those in the control group (26,026) with adjustment for socioeconomic status (SES) of general medical practices. Rate ratios were derived by means of logistic regression for the total trial population and for women first offered screening while younger than 50 years. Analyses were by intention to treat. FINDINGS: Initial unadjusted results showed a difference of just 13% in breast-cancer mortality rates between the intervention and control groups (156 deaths [5.18 per 10,000] vs 167 [6.04 per 10,000]; rate ratio 0.87 [95% CI 0.70-1.06]), but the results were influenced by differences in SES by trial group. After adjustment for SES, the rate ratio was 0.79 (95% CI 0.60-1.02). When deaths after diagnosis more than 3 years after the end of the study were censored the rate ratio became 0.71 (0.53-0.95). There was no evidence of heterogeneity by age at entry and no evidence that younger entrants had smaller or delayed benefit (rate ratio 0.70 [0.41-1.20]). No breast-cancer mortality benefit was observed for women whose breast cancers were diagnosed when they were younger than 50 years. Other-cause mortality rates did not differ by trial group when adjusted for SES. INTERPRETATION: Our findings confirm results from randomised trials in Sweden and the USA that screening for breast cancer lowers breast-cancer mortality. Similar results are reported by the UK geographical comparison, UK Trial of Early Detection of Breast Cancer. The results for younger women suggest benefit from introduction of screening before 50 years of age.

Does early growth delay occur in diabetic pregnancy?

OBJECTIVE: To identify the date of ovulation in pregnant women with Type 1 diabetes in order to assess the validity of the concept of early growth delay. DESIGN: Identification of ovulation by measurement of urinary luteinising hormone and assessment of fetal growth using ultrasound scan. SETTING: Diabetic pre-pregnancy and antenatal clinic in a teaching hospital. SUBJECTS: Twenty women with Type 1 diabetes who had attended a pre-pregnancy clinic. MEASURES: Urinary LH, by laboratory and kit methods, during conception cycles. Human chorionic gonadotrophin measured in early pregnancy. Early ultrasound scans by a single observer blind to menstrual and ovulation dates. OUTCOME: Gestation calculated from ovulation date and gestation estimated from menstrual dates, compared with gestation at age indicated by early ultrasound scan. RESULTS: When the date of ovulation was identified in 20 women with Type 1 diabetes there was no evidence of growth delay in any pregnancy. When gestation was estimated from menstrual dates there was apparent early growth delay in six pregnancies. CONCLUSION: This study, together with others discussed, indicates that early growth delay is probably an artefact of incorrectly estimated ovulation date.

Audit of a screening service for fetal abnormalities using early ultrasound scanning and maternal serum alpha-fetoprotein estimation combined with selective detailed scanning.

The objective of the study was the evaluation of a screening service for fetal abnormality using early ultrasound scanning to date and establish viability of the pregnancy combined with maternal serum alpha-fetoprotein estimation at 16 weeks and thereafter selective detailed scanning at 18-20 weeks based on clinical indication. The study was designed to be retrospective, emphasizing the possibility of diagnosis. Early scans were performed by radiographers and radiologists, detailed ones by radiologists and obstetricians with subspecialty training in prenatal diagnosis. The study was carried out in the ultrasound department of a large University Hospital. The subjects studied were all cases of abnormality identified pre- or postnatally in women delivering in the hospital over 4 years and to whom the screening service applied. Information was obtained from ultrasound and maternity records, birth notifications, pathology and autopsy reports and a special needs register. Cases were classified as not detectable, potentially detectable and usually detectable. Major fetal anomalies numbered 255 (total deliveries 19,497), a prevalence of 1.3%; 130 (51%) were diagnosed by ultrasound with 64% before 24 weeks and 36% later. Eleven chromosomal anomalies (4%) were diagnosed by genetic methods and 114 (45%) anomalies were not diagnosed antenatally. The sensitivity of the program was 37% before 24 weeks. Chromosomal anomalies, lesions of the central nervous system and cardiac defects were most common, followed by lesions of the gastrointestinal and urinary tracts. A large proportion of the detected and detectable anomalies were lethal.(ABSTRACT TRUNCATED AT 250 WORDS)

The Edinburgh randomised trial of breast cancer screening: results after 10 years of follow-up.

The Edinburgh Randomised Trial of Breast Cancer Screening recruited 44,288 women aged 45-64 years into the initial cohort of the trial during 1978-81, and 10 years of follow-up is now complete. A total of 22,944 women were randomised into the study group and were offered screening for 7 years; the remaining women formed the control group. After 10 years, breast cancer mortality is 14-21% lower in the study group than in the controls depending on the precise definition of the end point. These differences are not statistically significant; for breast cancer as the underlying cause of death the relative risk is 0.82 (95% confidence interval 0.61-1.11). Rates of locally advanced and metastatic cancer were substantially lower in the study group, but screening has failed to achieve marked reductions in rates of small node-positive cancers. Those women who accepted the final invitation to screening have been monitored over the 3 year period prior to their first screen under the UK service screening programme. Interval cases, expressed as a proportion of the control incidence, increased from 12% in the first year to 67% in the third year. The reduction in breast cancer mortality for older women (aged at least 50 years) is the same as that for the total study group for this duration of follow-up. For analyses of breast cancer mortality in younger women updates recruited to the trial from 1982 to 1985 (10,383 women with 6-8 years' follow-up) have been included. The reduction in breast cancer mortality for women aged 45-49 years at entry was 22% (relative risk = 0.78, 95% confidence interval = 0.46-1.31).

The efficacy of double reading mammograms in breast screening.

The effect of double reporting the screening mammograms of 31,146 women attending as part of the UK National Health Service Breast Screening Programme was analysed. Ninety per cent had their mammograms read by two of three experienced radiologists. Overall 1846 (5.9%) women were recalled for further assessment. Two hundred and sixty-one patients (0.8%) underwent surgical intervention resulting in the detection of 191 cancers (6.1/1000 women screened). The benign-to-malignant ratio was 1:3.6 (PPV 73.2%). Of the invasive cancers detected 72% had no histological evidence of axillary lymph node metastases. Twenty-one of the 191 cancers detected (10.4%) were missed by one of the two reporters. Six of these were invasive cancers < or = 1 cm in diameter. Comparison of those lesions detected by both readers to those detected by only one, showed readers were more likely to detect those lesions appearing as an opacity (65% vs 38%), but less likely to detect significant microcalcification (15% vs 33%). The difference between the two groups when taken as a whole, however, failed to reach statistical significance (chi 2 = 6.76, d.f. = 3, P = 0.08). In summary, double reporting resulted in an increase in sensitivity of 10%. However, there was a decrease in specificity of 1.8% with 569 women being recalled unnecessarily for assessment and biopsy of 13 benign lesions. The estimated resultant additional financial cost was 13773 pounds.

Assessment of non-palpable mammographic abnormalities: comparison between screening and symptomatic clinics.

A retrospective study found that a breast screening clinic generated fewer localization biopsies for non-palpable mammographic abnormalities than a symptomatic clinic (3.36 versus 9.89 per 1000 mammograms, respectively) and that a greater proportion of such biopsies were malignant. This study determined the reason for this difference. There were 108 of 304 (35.5 per cent) and 17 of 130 (13.1 per cent) carcinomas in women attending the screening and breast clinics respectively (relative risk 2.72 (95 per cent confidence interval 1.70-4.34)). This difference was regardless of age. The characteristics of the mammographic abnormality, the Wolfe pattern, a family history of breast carcinoma, parity and age at first pregnancy were similar in both groups. Women attending the screening clinic were referred for localization biopsy after assessment by clinicians and radiologists at a joint clinic; there was no joint assessment for patients attending the breast clinic. The same staff attended both clinics, although the proportion of time spent at each varied. This study suggests that all women with a non-palpable mammographic abnormality should be reviewed at a joint assessment clinic before localization biopsy is recommended.

Comparative pathology of breast cancer in a randomised trial of screening.

In the Edinburgh Randomised Breast Screening Project (EBSP) to December 1988 there were 500 cancers in the study population invited to screening and 340 cancers identified in the control population. The size and negative lymph node status characteristics of invasive cancers from the two populations were significantly different (P less than 0.05). The cancers detected by screening were predominantly 'early stage', with 16% noninvasive (PTIS) and 42% invasive stage I (pT1 node negative), whereas cancers were frequently 'late stage' (more than pT2) and inoperable in nonattenders (44%) and controls (36%). Grouped according to customary size ranges of invasive cancers, the proportion of cases lymph node positive differed in those screen detected compared with controls, but the benefit in favour of screen detection was not constant. In comparisons of cancers detected at prevalence and incidence screens, as a test of conformity with screening theory, no significant differences were apparent according to size and lymph node status, yet the characteristics of histological type of cancer discriminated significantly (P less than 0.05). When these same histological characteristics were used to compare survival, the capacity to separate invasive cancers into two groups having good and poor survival probabilities was evident, with a significant improvement for the screen detected poor survival group compared with controls (P less than 0.05).

Ultrasound evaluation of ectopic pregnancy including correlation with human chorionic gonadotrophin levels.

A total of 267 patients referred for ultrasound examination because of clinical suspicion of ectopic pregnancy were studied prospectively. The outcome was correlated with the ultrasound findings and human chorionic gonadotrophin levels using a quantitative serum assay. The value of the following in the diagnosis of ectopic pregnancy are assessed: ultrasound criteria for early diagnosis of intrauterine pregnancy before visualization of a viable fetus, the discriminatory zone of hCG and extrauterine abnormalities.

A comparison of fetal abdominal circumference measurements and Doppler ultrasound in the prediction of small-for-dates babies and fetal compromise.

A total of 145 pregnancies clinically suspected of being small-for-dates was studied at presentation with a single measurement of the fetal abdominal circumference and Doppler studies of the umbilical and arcuate arteries. The abdominal circumference measurement gave the best prediction of the small-for-gestational-age (SGA) baby (sensitivity 73%, umbilical artery sensitivity 47%, arcuate artery sensitivity 29%). The umbilical artery measurement gave the best prediction of antenatal fetal compromise; the performance of the tests was compared for a fixed sensitivity of 100% (i.e. all cases of antenatal compromise would be detected), the specificity of the umbilical artery measurement was 77%, abdominal circumference measurement 12% and arcuate artery measurement 2%. In our data, umbilical artery studies were not a sensitive predictor of the SGA baby but they did give an accurate prediction of the potentially compromised SGA fetus.

The effects of placental site on the arcuate artery flow velocity waveform.

Eighty-three consecutive patients were studied to determine the effect of placental site on the arcuate artery flow velocity waveform. The resistance indices derived from signals obtained from the placental side of the uterus were significantly lower than those derived from signals obtained from the nonplacental side. Doppler studies of the uteroplacental circulation should be performed preferably with knowledge of the placental site.

Use of risk factors to allocate schedules for breast cancer screening.

In an effort to reduce the cost of breast cancer screening several studies have explored the possibility of using risk factors to select a high-risk group of women and then restrict screening to that group. The results of these studies have been almost entirely negative and so it is not possible at present to classify any woman as at such low risk that she need not be screened. Nevertheless it is well known that some groups of women can be identified as being at higher risk than the general population. In this study it is assumed that each woman will be offered one screen at which risk factor information will be collected. The usual screening policy is then one of uniform intervention in which the interval to the next screen is the same for all women: the interval that is currently recommended in the UK is three years. An alternative is a risk strategy in which the time to the next screen depends on the woman's risk status; thus the total number of screens available to the population are distributed according to risk status. Using data from the Edinburgh randomised trial of breast cancer screening these policies have been compared. It is estimated that the proportion of cases detected by screening in the three years following the completion of the initial screening round could be raised from 60% to 67% by adopting a risk strategy. Lead time benefits are also quantified as are the comparisons for an established screening programme.

Umbilical artery Doppler waveform in pregnancies with uncomplicated intra-uterine growth retardation.

Seventy-four pregnancies with uncomplicated intra-uterine growth retardation were assessed at the time of diagnosis by Doppler ultrasound umbilical artery flow velocity waveform. The results were not disclosed to the clinicians. Only those pregnancies with a complete absence of pre-existing disease or pregnancy complications were included. Ten patients showed evidence of fetal compromise due to asphyxia either before or during labour. In all cases the umbilical artery flow velocity waveform had been abnormal, and this abnormality always preceded cardiotocogram abnormality by up to 5 weeks. Though the resistance index was significantly associated with birth weight (p less than 0.001), this relationship was clearly dependent on the compromised fetuses who tended to be very small, and the true association is probably between resistance index and compromise, with birth weight being an intervening variable.

"Bullet"-shaped head in fetuses with spina bifida: a pointer to the spinal lesion.

A "bullet"-shaped head, characterized by flattening in the parietal regions with pointing of the frontal bones, was noted in ultrasound examinations of fetuses with neural tube defects. In a series of 12 fetuses with spinal defects, this finding was present in nine. This abnormal head shape is a useful pointer to the spinal lesion.

The Edinburgh randomised trial of screening for breast cancer: description of method.

Edinburgh was selected as one of the centres in the UK Seven-year Trial of Breast Screening of women aged 45-65 which began in 1979. Subsequently, our study was extended to a randomised trial with its own control population within the city. Half the practices were randomly allocated for screening, giving a cluster sampling of women. The total number in the trial is 65,000. Women with previously diagnosed breast cancer are excluded. Women allocated for screening are invited to the clinic and screened according to the procedures specified in the U.K. protocol, having clinical examination every year and mammography on alternate years. The two modalities of screening are assessed independently and the role of nurses is being evaluated. Breast cancer incidence is monitored by pathology register and the local cancer registry office and deaths from the General Register office. Long-term follow-up will be obtained through flagging at NHS Central Register. To determine the value of screening, standard statistical methods will be used to compare breast cancer mortality rates in the whole of the screening population with that of the controls. This trial has a power of 83% of detecting a reduction in mortality of 35% after 7 years of follow-up and a power of 95% of detecting a similar reduction at 10 years (alpha = 0.05, one-sided test).

Oblique-view mammography: adequacy for screening. Work in progress.

Single oblique-view mammography has been recommended for screening purposes. The authors present data indicating that using the oblique view only can allow 11% of cancers to remain undetected. The smallest and potentially curable cancers are most likely to be overlooked in this way; any possible benefit of screening is thereby reduced. Data are also presented to show that 39% of women may require other views, for reasons not necessarily related to cancer detection. It is therefore recommended that all women have four-view mammography (oblique plus craniocaudal views of each breast) at their first screening visit.