Impairment of heart rate variability during paclitaxel therapy.

BACKGROUND: Paclitaxel, which has been reported to be effective in treating metastatic breast carcinoma and advanced ovarian carcinoma, has been associated with cardiac side effects. Therefore, the effect of paclitaxel on cardiovascular autonomic regulation was studied. METHODS: Twenty-four-hour ambulatory electrocardiogram measurements were recorded twice from 14 women with breast or ovarian carcinoma: once before paclitaxel treatment and once on the day after the second chemotherapy course. Heart rate variability (HRV) was assessed with spectral analysis. For the frequency domain analysis, HRV was assessed in the very low (0.005-0.040 hertz [Hz]), low (0.040-0.150 Hz), and high frequency (0.150-0.400 Hz) spectral components. RESULTS: The ratio between low frequency and high frequency HRV decreased (daytime values of 2.7% [standard deviation (SD) 1.6] vs. 1.7% [SD 0.91; P = 0.0098) after 2 courses of paclitaxel. The circadian fluctuation of HRV also decreased in all studied frequency components. CONCLUSIONS: The observed changes in spectral characteristics suggest that autonomic modulation of the heart rate is impaired after paclitaxel therapy. However, from these data it is not clear whether the observed changes are permanent or whether autonomic cardiac function returns to normal some time after treatment. Further studies are needed to examine whether these indices based on HRV can be used to detect those patients at risk for cardiac side effects during chemotherapy.

Screening for endometrial cancer in asymptomatic postmenopausal women with conventional and colour Doppler sonography.

OBJECTIVE: To evaluate endometrial thickness and uterine arterial flow measurement as predictors of endometrial cancer. DESIGN: Prospective study among a cohort of women invited to age-adjusted, population-based breast cancer screening by mammography. SETTING: City of Turku, Finland. POPULATION: 1074 postmenopausal women aged 57-61 years (mean 59 years). METHODS: Conventional and colour Doppler sonography. Endometrial biopsy was taken when the endometrial thickness (double layer) was > or = 4.0 mm, if the uterine artery pulsatility index was < or = 1.0 or if there was a fluid accumulation in the endometrial cavity. MAIN OUTCOME MEASURES: Detection of endometrial cancer in endometrial biopsy. Record linkage with the files of the Finnish Cancer Registry three and a half years after the first ultrasound examination. Major statistical results are based on the analysis of variance and logistic regression models. RESULTS: An endometrial biopsy was taken from 291 women (27%). One woman had endometrial tuberculosis, three an endometrial polyp, 16 endometrial hyperplasia, three endometrial carcinoma (Stage Ib), and one had cervical carcinoma (Stage Ib). One woman was diagnosed as having endometrial cancer Stage Ib two and a half years after screening; she had refused further examination after a positive screen. A second endometrial cancer (Stage Ib) was diagnosed three years after a negative screening result. CONCLUSION: Transvaginal sonography is confirmed to have a very high sensitivity for the detection of early endometrial carcinoma, but the specificity remains low. If endometrial cancer is to be detected at an early stage, further examinations should be carried out when the endometrial thickness is > or = 4.0 mm, especially when the woman has risk factors such as obesity, late menopause or current use of hormonal replacement therapy. Doppler sonography does not improve the detection of premalignant and malignant endometrial lesions compared with normal ultrasound.

Significance of a single CA 125 assay combined with ultrasound in the early detection of ovarian and endometrial cancer.

We evaluated the utility of a single CA 125 measurement in combination with transvaginal sonography for early detection of ovarian and endometrial cancer in asymptomatic postmenopausal women. A sample of peripheral blood was taken from 1291 apparently healthy postmenopausal women, who were examined by conventional and color Doppler ultrasound for early detection of ovarian and endometrial cancer. Serum CA 125 was determined in all samples 3 years later by the IMx CA 125 assay (Abbott Laboratories, Abbott Park, IL). The cutoff level based on the 99th percentile was 30 U/ml. Elevated values were controlled by repeat sonography and an additional determination of CA 125. Record linkage with the files of the Finnish Cancer Registry was performed 3 1/2 years after the primary sonographic screening. The mean CA 125 concentration was 8.1 U/ml (range 0-1410 U/ml). Fourteen of the 1291 women had a CA 125 level greater than 30 U/ml. None of these had signs of either endometrial or ovarian malignancy in the primary sonography screening. Among the other women three cases of endometrial carcinoma (all stage Ib) and one ovarian carcinoma (stage Ia with borderline malignancy) were detected by sonography. All these patients had a CA 125 value <30 U/ml, the mean value being 11.4 U/ml (range 7.5-16.7 U/ml). During follow-up of 3.5 years, one stage Ia ovarian carcinoma, one abdominal carcinomatosis, and two endometrial carcinomas (both stage Ib) were diagnosed. In these patients the mean value for CA 125 was 12.7 U/ml (range 2.5-30.9 U/ml) at the primary sonography screening. A single CA 125 measurement provides no advantage in the early detection of ovarian and endometrial cancer in asymptomatic postmenopausal women compared with transvaginal sonography. The vast majority of women with an elevated CA 125 value have some reason other than an ovarian or endometrial malignancy for this finding.

PAP smear after radiation therapy for cervical carcinoma.

Vaginal PAP smear is frequently used for the follow-up of cervical carcinoma after primary therapy. Irradiation induced atypia can interfere with cytological analysis and thus detection of a local recurrence, or simulate malignant atypia and cause unnecessary suspicion of recurrence. In this retrospective study we evaluated the reliability of cytological analysis and the reported frequency of irradiation induced atypia after radiotherapy. Eighty-nine patients treated for cervical carcinoma at Turku University Central Hospital during the years 1970-88 were included in the study. During the median follow-up of 34 months a total of 697 PAP smears were taken with a median of 7.8 samples per patient. During the follow-up 44 (50%) patients had a recurrent disease, which was local in 17 (39%) cases. Nine out of 12 PAP smears taken 0-60 days before detection of a local recurrence showed class III-V cellular atypia. However, three PAP smears showed class I-II, and were therefore false negative. The rate of false positive samples was only 3%. In 567 PAP smears irradiation induced atypia was indicated as present/not present (+/-) and it was positive in 89 (16%) samples. The detection rate was considerably higher (75%) in class II samples than in rest of the material. Irradiation induced atypia was detected in 28% of the PAP smears taken during the first four months after radiotherapy and the rate decreased thereafter. Cytological analysis of vaginal PAP smear was a reliable indicator of recurrence in most cases and is a valuable tool for the detection of local recurrence of cervical carcinoma after primary radiotherapy.

Endometrial fluid accumulation in asymptomatic postmenopausal women.

Postmenopausal endometrial fluid accumulation was considered in the past to be related to cancer of the genital organs. Our purpose was to evaluate its prevalence, and its association with cervical stricture, use of hormone replacement therapy and endometrial pathology. A group of 1074 asymptomatic postmenopausal women aged 57-61 (mean 59) years was examined by transvaginal sonography with color Doppler imaging. Women who had an endometrial fluid accumulation underwent endometrial biopsy. Statistical analysis was mainly based on analysis of variance. Endometrial fluid accumulation was found in 134 women (12%). Women using only estrogen as hormone replacement therapy had a relative risk of 3.5 of endometrial fluid accumulation. In 12 women (9%), a cervical stricture precluded endometrial sampling. Six abnormal histopathological samples were found (5%): two endometrial polyps, one cystic hyperplasia, two adenomatous hyperplasias but only one adenocarcinoma. One further patient with endometrial cancer was registered by the Finnish Cancer Registry 2.5 years later in a woman who had refused endometrial sampling. Endometrial fluid accumulation is quite a common finding on transvaginal sonography among asymptomatic postmenopausal women and the process may be multifactorial. Cervical stricture is not the most important etiological factor. The use of estrogen replacement therapy increases the risk of endometrial fluid accumulation; however, it is rarely a sign of malignancy.

High-dose chemotherapy with autologous stem cell support in advanced ovarian cancer.

Since 1981, over 300 patients reported with advanced or refractory ovarian cancer have been treated with high-dose chemotherapy supported by autologous bone marrow or peripheral blood stem cell transplantation. Partial or complete clinical response has been reported in 54-100% of the cases, but the median duration of the response in the majority of patients has been only a few months. It is obvious from the available data that high-dose regimens supported by autologous stem cell transplantation (ASCT) are not capable of inducing long-term survival in patients with heavy tumour burden or chemoresistant ovarian cancer. Recent reports on nearly 100 patients have described results of the use of high-dose chemotherapy as first-line treatment for patients with optimally debulked disease or negative second-look laparotomy. Response rates and survival have been better when compared to historical controls, but the efficacy of this treatment modality in inducing durable remission has not been tested in randomized trials. Most of the ongoing trials presented briefly in this review have been designed to evaluate the potential of high-dose therapy as first-line treatment in preventing the development of resistant tumour clones and recurrence. The role of sequential high-dose chemotherapy with ASCT as a part of primary treatment or as salvage therapy for chemosensitive recurrent disease is also under investigation.

Transdermal estrogen for female stress urinary incontinence in postmenopause.

OBJECTIVE: To evaluate the effect of transdermal estrogen for stress urinary incontinence in postmenopause. STUDY DESIGN: An open within patient, dose-finding study with transdermal 17-beta-estradiol combined with cyclic medroxyprogesterone acetate was conducted over 9 months in 21 patients (mean age 57.3 years) suffering from urodynamically verified mild to moderate stress incontinence without detrusor instability. RESULTS: Subjective improvement was noted in 16 out of 21 patients (76%). The dose level of 50 micrograms was better tolerated than 100 micrograms and sufficient enough to achieve continence. CONCLUSION: Transdermal estrogen therapy plays an adjuvant role in conservative therapy for mild to moderate stress urinary incontinence in postmenopausal women.

Evaluation of ovarian findings in asymptomatic postmenopausal women with color Doppler ultrasound.

BACKGROUND: To evaluate the prevalence and significance of abnormal ovarian findings in asymptomatic postmenopausal women, screening for ovarian cancer with color Doppler ultrasound was performed. METHODS: One thousand three hundred sixty-four asymptomatic women aged 56-61 years (mean, 59 years) were examined by color Doppler sonography. Ninety-six percent of the examinations were transvaginal and 4% transabdominal. The criteria for abnormality were an ovarian volume 8 cm3 or greater, nonuniform echogenicity, and/or pulsatility index (PI) of the ovarian artery or tumor vessel, if present, 1.0 or less. Repeat sonograms were performed 1-3 months later on all patients with abnormal findings, and exploratory laparotomy was performed if a malignant tumor was suspected. RESULTS: Abnormal ovarian findings were detected in 160 women (12%). At the time of repeat sonogram there were 28 persisting abnormalities (2%). At that time, the ovary was regarded as normal if it still contained a small clear cyst with an unchanged greatest dimension of less than 20 mm. Three women had a low PI value but all had also abnormal ovarian sonographic morphology. Two ultrasound-guided cyst punctures were performed and three patients had surgery; one benign serous cyst, one benign serous cystadenoma, and one serous cystadenoma of borderline malignancy were detected. The remaining abnormal findings disappeared or remained unchanged during a minimum follow-up of 2 years. One case of Stage IA ovarian cancer has been reported 2 years after a negative screening and one abdominal carcinomatosis 2 1/2 years after a negative screening result. CONCLUSIONS: There is a high frequency of small ovarian cysts in asymptomatic postmenopausal women. A large percentage of these cysts regress spontaneously or remain unchanged. Transvaginal color Doppler ultrasound is an effective method for detecting these lesions. Color Doppler does not increase substantially the number of operations for benign reasons. However, as a primary screening modality, the conventional sonography seems to be quite sufficient.

A longitudinal study of screening for endometrial cancer by endometrial biopsy in diabetic females.

Diabetics are at high risk of developing endometrial cancer; the relative risk of endometrial cancer in diabetics is fourfold in comparison to non-diabetic controls. The purpose of this longitudinal study was to evaluate the effectiveness of screening asymptomatic diabetic females in terms of the premalignant and malignant endometrial findings, and to try to determine the optimal screening interval. In 1980-1981, a group of 462 diabetic females was identified and registered. One half of them (237) was invited to be screened. Endometrial samples were taken by using Vabra aspiration. The results of this first randomized screening in 1980-1981 have been published elsewhere. At that time 124 females participated. The remaining 225 females acted as an unscreened control group. Eight years later (1988-1989), both groups were invited to be screened. The Pistolet aspiration method was used. At this stage, group 1 (screened in 1980-1981) consisted of 78 females, and group 2 (not screened in 1980-1981) consisted of 148 females. In 85% (193/226) of the females, the uterine cavity was reached with the Pistolet instrument; 96% of the females found the pain acceptable. In the group screened twice (group 1), no pathologic lesions of the endometrium were found in the second screening. In the group screened for the first time (group 2), one female had endometrial adenocarcinoma (0.8%), one had complex hyperplasia without atypia (0.8%) and four had endometrial polyps (3.3%). In 165 cases of 193, both a cytologic and a histologic specimen were available. In 130 cases (79%) the cytology was of class I, including the one endometrial adenocarcinoma. In three cases (2%) it was of class II and in one case (1%) of class III. Endometrial biopsy by Pistolet aspiration was a method highly acceptable by the patients for examining the endometrium. However, cytologic examination was not able to show the existing endometrial adenocarcinoma. One endometrial sampling of asymptomatic diabetic females during early menopause could detect the bulk of the occult, slowly progressing lesions of the endometrium. Such screeening might be most efficient in terms of cost-benefit ratio.

Effects of external radiotherapy on uterine blood flow in patients with advanced cervical carcinoma assessed by color Doppler ultrasonography.

BACKGROUND: This study was designed to evaluate radiation-induced changes in tumor blood flow by color Doppler ultrasonography. METHODS: Color Doppler examination was performed on 14 patients with advanced cervical carcinoma treated with external radiotherapy. The total dose of radiation varied from 30 to 65 Gy and was given as 1.9 Gy daily fractions, 5 days/week. Tumor vascularity and blood flow impedance were measured by one pretreatment and five follow-up examinations. RESULTS: At the baseline examination, 11 of 14 patients had very low tumor blood flow impedance (< 0.70). Radiotherapy caused a significant decrease in tumor vascularity (P = 0.0001) and in presence of very low blood flow impedance. The decrease of tumor vascularity during the treatment was associated with better outcome, whereas persistence of excessive vascularity or of vessels with low blood flow impedance at the end of radiation was associated with modest therapeutic response. Eight of 10 patients with increased tumor vascularity at the end of radiation needed further treatment or died of disease. Only one of four patients with normal vasculature at the end of radiotherapy needed further treatment and all four were clinically disease free during the follow-up (mean, 13 months; range, 6-26 months). CONCLUSIONS: These results suggest that color Doppler ultrasonography may be useful in early assessment of therapeutic response during radiotherapy and in for planning individualized treatment schedules.

The role of cul-de-sac aspiration cytology in the follow-up of ovarian cancer.

The methods most often used for follow-up of ovarian cancer are physical examination, CA-125 measurement and ultrasonography or computed tomography. In the present study the role of cul-de-sac aspiration cytology as a supplementary method was evaluated. We analyzed the records of 110 stage I-IV ovarian cancer patients who had undergone cul-de-sac aspiration as a part of their follow-up schedule after the primary treatment. During the median follow-up of 5 years altogether 577 cul-de-sac aspirations were performed with a median interval of 9 months. Only in 2 cases the obtained sample was insufficient for evaluation. Twenty patients had cul-de-sac cytology > or = class III at some point during the follow-up. In 12 cases the preceding or subsequent CA-125 values taken within 3 months were < 35 U/l. In 7 cases CA-125 values increased later, but in 5 cases the tumour marker values remained within normal range during the entire follow-up. Nine out of these 12 patients had a clinical recurrence later on, but 3 patients had no evidence of the disease. Twenty-seven recurrences were detected during the follow-up. Cul-de-sac aspiration cytology was the first or the only indication of recurrence in 9 cases (33%) and is a useful supplementary method in the follow-up of ovarian cancer.

Primary breast and colon cancer associated with endometrial or ovarian cancer.

Patients with endometrial or ovarian cancer have an increased risk of breast or colon cancer and vice versa. To study the individual and age-related characteristics of patients with a combination of these malignancies, we reviewed the hospital records of fifty-three patients who had endometrial or ovarian cancer diagnosed at the Turku University Central Hospital in 1977-1991, and who had a preceding, concomitant or subsequent diagnosis of breast or colon cancer. Forty-nine patients had two and four patients had three primary cancers. Breast cancer patients presenting with subsequent ovarian carcinoma had a clearly lower mean age at first cancer diagnosis than the general population mean for breast cancer (50.0 years vs 61.1 years). The mean age of these patients at the time of diagnosis of ovarian cancer was not lower than the general population mean for ovarian cancer (62.0 years vs 61.1 years). A genetic predisposition to both breast and ovarian cancer has been reported previously. More attention should be paid to breast cancer patients' family histories with respect to ovarian cancer, especially if the patient is premenopausal. This might help to identify women at risk of getting ovarian cancer later in life.

Long-term effects of hormone replacement therapy on the uterus and on uterine circulation.

OBJECTIVE: Our purpose was to study the effects of postmenopausal hormone replacement therapy on the uterus and uterine circulation. STUDY DESIGN: The study population consisted of 432 women, 58 to 59 years of age. Color Doppler ultrasonography with a transvaginal probe was used to measure the size of the uterus and the uterine artery pulsatility index. RESULTS: The mean endometrial thickness in group 1 (controls without hormone replacement therapy) was significantly thinner compared with group 2 hormone replacement therapy and with group 3 after discontinuance of hormone replacement therapy. The mean uterine artery pulsatility index was lower both in group 2 and 3 compared with group 1. When hormone replacement therapy was initiated 2 to 10 years after menopause, the endometrial thickness did not differ from that among those who had started hormone replacement therapy earlier, but the pulsatility index was significantly higher. There was positive correlation between the size of the uterus and the pulsatility index in group 1, but the correlation was negative in group 2. In general, the duration of hormone replacement therapy had no effect on the pulsatility index. Estrogen users had a significantly thicker endometrium compared with estrogen-progestogen users. The pulsatility index was highest in the estrogen users with progestogen added every month. CONCLUSION: The duration, onset of treatment in relation to menopause, discontinuance of hormone replacement therapy, and mode of treatment modify both the normal postmenopausal endometrial thickness and the uterine vascular resistance.

Mass screening for endometrial cancer directed in risk groups of patients with diabetes and patients with hypertension.

BACKGROUND: The interest in mass screening programs for the early detection of endometrial cancer (EC) has grown with the rising incidence of this disease. Preliminary programs directed at asymptomatic women with only one risk factor, i.e. age, have not been cost-effective. METHODS: In the current study, 597 asymptomatic women from 45-69 years of age with diabetes and/or hypertension were screened by Vabra (Berkeley Medevices Inc., Berkeley, CA) aspiration. RESULTS: Among the women with diabetes, 6.3% preinvasive lesions of the endometrium were found. This is significantly more than the rate among women with hypertension, which was 1.3% (P < 0.01). CONCLUSIONS: Regular mass screening programs for the early detection of EC should be directed at asymptomatic diabetic women 45 years of age or older. This study does not indicate that similar screenings would be effective for women with hypertension.

Encouraging rates of fertility after ectopic pregnancy.

A follow-up study (4 to 8 years) on fertility of 110 patients seeking pregnancy after ectopic pregnancy (EP) showed normal delivery in 65%, recurrent EP in 20%, and infertility in 15%. Delivery rates were better in patients who were under age 30 years, used an IUD at the time of operation for EP, and underwent conservative operative treatment for acute EP. The subsequent intrauterine pregnancy rates of EP patients who had used an IUD at the time of ectopic nidation were the same (92%) as after removal of IUD in the healthy population. It appears that IUD plays a predisposing role in EP only when in use. The study also shows that modern diagnostic and therapeutic procedures are beneficial for improving subsequent fertility rates after EP. These fertility rates are highly encouraging with respect to the massive increase of EP in the Finnish population.

Myelin-associated glycoprotein in the developing human retina.

The immunohistochemical presence of myelin-associated glycoprotein (MAG) in Müller cells of the developing human retina was examined with rat monoclonal antibodies to MAG and the peroxidase antiperoxidase (PAP) method of Sternberger. Retinas of various developmental stages ranging between 9-31 gestational weeks were stained. There was no staining in the retinas of 9-12-week embryos. Between 13-16 gestational weeks the staining was faint and located mostly in the inner and middle portion of the retina, primarily around the optic nerve head. After midterm, Müller cells invariably stained through all retinal layers. The staining increased gradually up to the twenty-third gestational week, when it reached the level found in the retinas of newborn children.