Immunolymphoscintigraphy and immunoscintigraphy of ovarian and fallopian tube cancer using F(ab')2 fragments of monoclonal antibody OC 125.

We have used immunolymphoscintigraphy (ILS) alone or in combination with immunoscintigraphy with 131I-labeled F(ab')2 fragments of monoclonal OC 125 antibodies to improve detection of retroperitoneal lymph node metastases of ovarian and fallopian tube cancer. ILS was carried out with bilateral dorsopedal s.c. injections on nine patients and with bilateral iliopelvic injections into the ischiorectal fossa on two other patients. Radioimaging was performed 2-4 times between 0 and 5 days. An additional dose of labeled antibody fragments was given i.v., and imaging was done 2-3 days later. Conventional immunoscintigraphy without preceding ILS was carried out on another nine patients. Dorsopedal ILS improved detection of pelvic and paraaortic lymph node metastases. Malignant lymph nodes were detectable as early as 3 h after s.c. injection of the tracer. Combined results of ILS and immunoscintigraphy in 16 surgically verified cases indicated a true positive finding in 9 patients, true negative finding in 5, false positive in one, and false negative in 1. Calculated from these figures the sensitivity, specificity, and accuracy of the method were 90, 83, and 88%, respectively. Involved lymph nodes were found more frequently in those patients whose serum CA 125 concentration was elevated demonstrating that an elevated serum CA 125 level does not preclude successful radioimmunodetection.

Presence of alpha 2-macroglobulin in normal but not in malignant human syncytiotrophoblasts.

alpha 2-Macroglobulin (alpha 2M) was demonstrated in normal syncytiotrophoblasts of both early and full-term human placentas using immunocytological staining. alpha 2M was also detected in hydatidiform moles, the benign tumors of proliferating syncytiotrophoblasts. In contrast, no alpha 2M was detected in invasive moles or choriocarcinomas. In culture conditions, both normal syncytiotrophoblasts and choriocarcinoma cells, identified by production of human chorionic gonadotropin, were negative when stained for alpha 2M or when studied using metabolic labeling and immunoprecipitation or radioimmunoassay. However, alpha 2M was taken up from added human serum by the cultured syncytiotrophoblasts, whereas choriocarcinoma cells remained negative also under these conditions. The possible role of alpha 2M in the regulation of proteolysis in cell invasion is considered.

Epidemiology of hydatidiform mole in Finland, 1975 to 2001.

PURPOSE: Broad variations in the incidence of gestational trophoblastic diseases have been reported in different parts of the world. Recent time trends in the incidence of hydatidiform mole in Western countries have not been elucidated. We studied the epidemiology of hydatidiform mole in Finland over a period of 27 years. METHODS: Women reported to have hydatidiform mole from 1975-2001 were identified from the National Research and Development Center for Welfare and Health. Women with choriocarcinoma were identified from the Finnish Cancer Registry. RESULTS: We identified 1659 cases of hydatidiform mole between 1975 and 2001. This gives an incidence of 73/10(6) women or 984/10(6) deliveries. The overall incidence remained fairly constant over the study period. The incidence was higher in women below 20 years and above 39 years than in women in the other age groups. Forty-nine percent of choriocarcinomas identified during the study period were associated with a preceding hydatidiform mole. The risk of choriocarcinoma after a hydatidiform mole was 2.2%. CONCLUSIONS: The incidence of hydatidiform mole in Finland follows the same patterns as in other Western countries. The incidence has not changed considerably in recent decades.

Acute changes in serum prolactin concentration have no effect on the secretion of progesterone, estradiol, or chorionic gonadotropin during early pregnancy.

The relationship between the circulating levels of PRL and progesterone, estadiol, and hCG was studied during the first half of pregnancy. The subjects were 1) nine hyperprolactinemic women who conceived during bromocriptine treatment and whose treatment was discontinued at the 7th to 11th weeks of gestation; 2) five women given chlorpromazine during the 11th to 12th weeks of pregnancy; and 3) four pregnant women give bromocriptine during the 11th to 12th weeks of pregnancy. In group 1, discontinuation of bromocriptine resulted in elevated serum PRL concentrations, but this was not associated with any significant changes in the circulating levels of estradiol, progesterone, and hCG. In group 2, chlorpromazine increased the serum PRL concentration but had no effect on serum estradiol, progesterone, or hCG concentrations. In group 3, bromocriptine decreased the serum PRL level, but this was not associated with any alteration in steroid hormone or hCG levels. Our results show that during early pregnancy acute moderate changes in the serum PRL concentration do not affect placental hormone secretion.

Relationship between carbohydrate metabolism and serum insulin-like growth factor system in postmenopausal women: comparison of endometrial cancer patients with healthy controls.

Insulin is a major regulator of circulating insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1), suppressing the hepatic production of IGFBP-1. Postmenopausal age, obesity, hypertension, and impaired glucose tolerance, which are known risk factors for endometrial cancer, are all associated with hyperinsulinemia and insulin resistance. In this study, we investigated the relationship among serum insulin, glucose, insulin-like growth factors (IGF-I and IGF-II), and IGFBP-, -2, and -3 in 32 nondiabetic postmenopausal women with endometrial cancer and in 18 healthy controls. The mean fasting levels of glucose and insulin were higher, whereas the mean basal IGF-I, IGF-II, and IGFBP-3 levels were lower in the endometrial cancer patients than in the healthy control subjects. The mean fasting IGFBP-1 and IGFBP-2 levels did not differ between the groups, and no correlation was found between fasting insulin and IGFBP-1 concentrations or between insulin and IGFBP-2 concentrations in either of the study groups. During an oral glucose tolerance test, the mean glucose levels at 1 and 3 h as well as the mean insulin level at 3 h were significantly higher in the endometrial cancer patients than in the controls, and the area under the glucose curve was larger in the first group. An oral glucose load resulted in a similar fall in serum IGFBP-1 levels in endometrial cancer patients and controls (51% and 55% at 3 h). When the cancer patients were divided into two subgroups according to the body mass index (kilograms per m2), the obese group had higher glucose and insulin indices than the nonobese group. No difference was found by the same measures in healthy controls. The fasting serum IGFBP-1 levels tended to be lower in the obese than in the normal weight subjects, but the difference did not reach statistical significance. In summary, these results provide preliminary evidence that the inverse relation between fasting insulin and IGFBP-1, well established in children and young adults, disappears in elderly women, although short term suppression by insulin still occurs. Further, our data indicate that in addition to carbohydrate metabolism, postmenopausal women with endometrial cancer have alterations in their circulating IGF system compared to controls.

Pregnancy-specific beta 1-glycoprotein and chorionic gonadotropin-like immunoreactivity during the latter half of the cycle in women using intrauterine contraception.

In a cross-sectional study, the serum levels of pregnancy-specific beta 1-glycoprotein (PSBG), hCG, human LH, and progesterone were measured by RIAs during 94 mid or late luteal phases of 69 women using oral contraceptives. Subsequent spontaneous menstruation took place in every cycle. None of the women using oral contraceptives had any PSBG or hCG-like immunoreactivity in serum. In women with intrauterine devices, PSBG was found in six cycles (6.4%) and hCG-like immunoreactivity was demonstrated in one cycle only, where PSBG also was present. In two out of six PSBG-positive cycles, menstruation was delayed by 5 and 16 days. Although rare, the transient occurrence of trophoblastic antigens in women using intrauterine contraception is taken as evidence for an occult pregnancy in these apparently infertile cycles.

PIP: Serum levels of pregnancy-specific beta-1-glycoprotein (PSBG), human chorionic gonadotropin (hCG), human luteinizing hormone (LH), and progesterone were measured by radioimmunoassays during 94 mid- or late luteal phases of 69 women using IUDs and 34 women using oral contraceptives (OCs) in a cross-sectional study. hCG-like immunoreactivity was found in 1 of 94 cycles (1.1%) of women using IUD contraception, and in none of those taking OCs. The positive hCG reaction was found on Day 27 of the cycle. In the hCG-positive sample, hCG concentration was 19 mIU/ml. Cross-reaction by LH was unlikely since the LH concentration was 82 ng/ml, well below the cross-reacting level of the assay. PSBG was found in 6 of 94 cycles (6.4%) of IUD users, and in none of OC users. Levels varied from 11-21 ng/ml, and PSBG was found on Days 24-27 of the cycle. 1 cycle demonstrated both hCG and PSBG, and the PSBG concentration was 15 ng/ml. In trophoblastic antigen-positive IUD cycles, menstruation was delayed from the expected date by 3 or more days in 2 cases. In the case where both markers were found, menstruation was delayed by 16 days. Aside from menstrual delay in 2 subjects, no typical changes were noted in the bleeding pattern of those cycles where trophoblast-specific antigens were detected. Although rare, the transient occurrence of trophoblastic antigens in women using IUDs was taken as evidence for occult pregnancy in these apparently infertile cycles.

Monoclonal antibody defining a human syncytiotrophoblastic polypeptide immunologically related to mammalian retrovirus structural protein p30.

Antigenic material previously detected in human placental trophoblastic cells by immunoperoxidase staining using a goat antiserum against the feline RD114 retrovirus structural protein p30 was isolated by immunochromatography from normal syncytiotrophoblast. The antigen was used to immunize mice, and of the monoclonal antibodies produced by murine hybridomas an IgG1 was selected which reacted in enzyme immunoassay with the syncytiotrophoblast antigen and with purified RD114. This antibody, designated HPS-1, stained normal and neoplastic syncytiotrophoblasts in a manner similar to that of the goat antibodies, detected in immunoblotting a Mr = 130 000 polypeptide in cultured human choriocarcinoma cells and reacted in spot immunoblotting tests with purified preparations of mammalian retroviruses but not with an avian retrovirus. The polypeptide antigen may represent activation of human endogenous retroviral genes in syncytiotrophoblast.

Predominance of serum antibodies to synthetic peptide stemming from HPV 18 open reading frame E2 in cervical adenocarcinoma.

AIMS: To determine if there are type specific differences in serum antibody responses to synthetic peptides derived from human papillomavirus (HPV) open reading frame (ORF) E2 in patients with cervical carcinoma. METHODS: Diagnostic phase sera from 88 age-matched women with cervical adenocarcinoma (AC), cervical squamous cell carcinoma (SC), ovarian cancer (OC) or no gynaecological malignancy were available. Serum IgG and IgA antibodies to synthetic peptides corresponding to a residue of HPV 6, 11, 16, and 18 ORF E2 18 amino acids long and a control peptide from mumps virus were determined by ELISA. RESULTS: Both IgA and IgG antibody positivity to the HPV 18 peptide were associated with increased risk (9.0-fold, confidence limits 1.5-199) for AC. IgA positivity to HPV 11, 16, and 18 peptides was associated with an increased risk for SC. However, the association of IgG antibodies to HPV 16 peptide with SC was not significant. IgA or IgG antibodies to HPV 6 or mumps virus peptides were not associated with increased risk for AC, SC, or OC. CONCLUSIONS: These results suggest a specific role for HPV 18 in AC. Differences in antibody responses to HPV peptide in AC and SC suggest immunopathogenetic differences between the two types of cervical carcinoma.

Conservative treatment of ectopic pregnancy.

As a conservative nonsurgical treatment of an early ectopic pregnancy, local prostaglandin, parenteral or local methotrexate, local hyperosmolar glucose, and also expectant management have been used successfully in selected cases. The success rate of conservative treatment has been 71%-100% and that of tubal patency after different kinds of conservative treatment 72-93% of patients. In the present study of expectant management in early ectopic pregnancy in patients with decreasing serum hCG levels, spontaneous resolution was observed in 64.6% of patients and in the total series of 207 ectopic pregnancies in 15.0% of patients. Expectant management of early ectopic pregnancy is recommended when emergency surgery is not needed on admission and the serum hCG level is decreasing as noted in two consecutive estimations with an interval of 1-2 days.

Effect of nicotine on fetal prostacyclin and thromboxane in humans.

To study the effect of nicotine on fetal prostacyclin and thromboxane A2, specimens from the umbilical arteries of infants born to healthy nonsmoking mothers were superfused in the absence or presence of nicotine (50 to 10,000 micrograms/mL), and the releases of 6-keto-prostaglandin F1alpha (a break-down product of prostacyclin) and thromboxane B2 (a metabolite of thromboxane A2) were measured. The baseline production of 6-keto-prostaglandin F1alpha (63.9 +/- 8.8 ng/minute per gram of dry weight tissue, mean +/- SE, N = 10) or that of thromboxane B2 (1.3 +/- 0.2 ng/minute per gram, N = 10) were unaffected by nicotine. To study the effect of nicotine on thromboxane A2 synthesis by the fetal platelets, thrombin-induced platelet aggregation and consequent thromboxane A2 synthesis were allowed to occur in the whole cord blood in the absence or presence of nicotine (10 to 500 micrograms/mL). Nicotine inhibited concentration dependently platelet thromboxane A2 synthesis from the baseline level (107.3 +/- 7.1 ng/mL) by 15 to 93%. This inhibition was also seen in thromboxane A2 synthesis starting from exogenous arachidonic acid, suggesting that nicotine inhibits either cyclooxygenase and/or thromboxane A2 synthetase in the fetal platelets. Thus, nicotine is hardly responsible for maternal smoking-induced changes in fetal prostacyclin formation.

Elevated prolactin levels in oral contraceptive pill-related hypertension.

Twenty women whose blood pressure became elevated during oral contraceptive treatment had higher serum prolactin levels (31 +/- 5.3 microgram/liter) than did 20 normotensive pill takers (16.1 +/- 1.8 microgram/liter) and 20 women who were not taking the pill (14 +/- 1.1 microgram/liter), and the higher level was maintained (30 +/- 3.5 microgram/liter) after the pill was discontinued and blood pressure had become normal. This increase in prolactin levels was not related to differences in age or mode of treatment, and it is thought to reflect an alteration in dopaminergic transmission in patients with pill-related hypertension.

PIP: Serum prolactin levels were examined in women with pill-associated hypertension since changes in serum prolactin levels also reflect changes in transmission of dopamine. 20 women whose blood pressure elevated during use of oral contraceptives had higher serum prolactin levels than did 20 normotensive pill users (31 vs. 16 mcgm per liter) and 20 nonpill users (14 mcgm); the correlation of elevated arterial pressure with elevated prolactin was P.005. After the pill was discontinued, the blood pressure of each hypertensive woman dropped to normal range by the end of the first posttreatment cycle; however, the serum prolactin levels continued to be higher than those of normotensive pill users and those of nonpill users. In 1 patient an elevated prolactin level persisted after 12 months of nontreatment (50 mcgm/liter). This increase in serum prolactin level was unrelated to age differences or mode of treatment; hence, it was thought to reflect an alteration in dopaminergic transmission in patients with oral contraceptive-related hypertension.

Identification of choriocarcinoma by the hCG beta-to-hCG proportion in patients with delayed diagnosis caused by contraceptive use.

The use of contraceptives, especially subdermal implants and levonorgestrel-containing intrauterine device (IUD), often cause irregular bleeding. Thus, they may mask unsuspected choriocarcinoma, which also often presents with abnormal bleeding. Choriocarcinoma is mostly curable with combination chemotherapy, but delayed diagnosis can lead to treatment failure. Two cases of choriocarcinoma with considerable delay in diagnosis, due partly to contraceptive use, are reported. The proportion of human chorionic gonadotropin-beta (hCG beta) and total hCG immunoreactivity showed that the proportion of hCG beta was elevated at presentation in both cases.

PIP: Irregular bleeding is a common side effect of the use of contraceptives, especially subdermal implants and the levonorgestrel-containing IUD. However, these methods may mask choriocarcinoma, which also presents with abnormal bleeding. About 50% of choriocarcinoma cases are associated with a complete hydatidiform mole, 25% follow an abortion or tubal pregnancy, and 25% follow a term gestation. Although this carcinoma is generally curable with combination chemotherapy, delayed diagnosis can produce a fatal outcome. Presented are two cases of gestational choriocarcinoma drawn from a sample of 27 Finnish women with a molar pregnancy in which the method of contraception caused a considerable delay in diagnosis. In both cases, the proportion of beta-human chorionic gonadotropin (hCG) was elevated (6% of total hCG immunoreactivity) at hospital presentation. At diagnosis (by dilatation and curettage for irregular bleeding) 15 months after Norplant insertion, the first patient had a beta-hCG proportion of 80%. Even after chemotherapy, this ratio remained in the 40-50% range and the woman died 2 years after diagnosis. The second patient underwent a dilatation and curettage for irregular bleeding 9 months after insertion of a levonorgestrel-releasing IUD. The proportion of beta-hCG was 9%, indicating malignant trophoblastic disease, but this ratio returned to normal after successful chemotherapy. These findings confirm that the proportion of beta-hCG out of total hCG immunoreactivity differentiates between malignant and benign disease. Determination of this proportion is thus recommended in all women with molar pregnancies to identify those who are likely to develop choriocarcinoma.

Comparison of enoxaparin, a low-molecular-weight heparin, and unfractionated heparin, with or without dihydroergotamine, in abdominal hysterectomy.

The effects of administration of low-molecular-weight heparin (enoxaparin 20 mg) once a day, of unfractionated heparin (5000 IU twice a day, and of unfractionated heparin (2500 IU) plus dihydroergotamine (0.5 mg) twice a day were assessed in 100 patients undergoing abdominal hysterectomy. The test medications were given subcutaneously 2 hours before operation and for 3 days thereafter. There were no thromboembolic complications. Intraoperative blood loss, wound haematomas and blood loss via drains during four days after operation were similar in the three groups. None of the 37 patients receiving enoxaparin experienced major postoperative bleeding. Six out of 31 patients receiving unfractionated heparin without dihydroergotamine and two out of 32 patients receiving dihydroergotamine in addition experienced major bleeding necessitating re-operation and/or blood transfusion, (P < 0.05). Enoxaparin caused less major bleeding than unfractionated heparin with or without dihydroergotamine in patients undergoing hysterectomy.

Forearm blood flow in the normal menstrual cycle.

The peripheral hemodynamics of the normal menstrual cycle were investigated in twenty-two healthy young women. The total blood flow in a segment of the forearm, as measured by plethysmography and local vascular resistance, were estimated both at rest and during postischemic reactive hyperemia in eight subjects. Resting cutaneous blood flow was measured in 14 subjects using 133Xe clearance method. No significant differences were observed between the results obtained in the pre- and postovulatory phases of the cycle.

The acute effect of smoking on uteroplacental blood flow in normotensive and hypertensive pregnancy.

The acute effect of smoking on uteroplacental blood flow was studied by the 133Xe method in 12 normotensive and 11 hypertensive pregnant women at term. A standard cigarette caused an acute decrease in intervillous blood flow in the normotensives but normalized within 15 minutes. In the other group, smoking produced a progressive increase in this flow, whose basal presmoking value lower in the hypertensive women. The myometrial blood flow was equal in both groups before smoking but significantly higher in the hypertensive group immediately afterwards. Smoking produced a constant increase in systolic, diastolic and mean arterial blood pressure in the normotensive women. In the other, diastolic and mean arterial blood pressure increased only temporarily, while systolic blood pressure remained unchanged. Heart rate increased in both groups. Repeated decreases in the intervillous blood flow could explain growth retardation of the fetus and some other complications of pregnancy in normotensive smokers. The authors assume that postischemic reactive hyperemia in the uterine vessels caused the increased flow in hypertensive pregnant women after smoking but cannot recommend it as beneficial because of the increased placental transfer of the harmful elements found in tobacco smoke.

Hemodynamic effects of oral contraceptives during exercise.

The effects of a combined oral contraceptive pill on female hemodynamics during exercise were studied in 14 young, healthy women. The increase in blood volume, stroke volume, and cardiac output during exercise was significantly greater during combined oral contraceptive therapy than when the patients were not taking the pill. The use of combined oral contraceptive pills may be advantageous to the physical fitness of female athletes.