[Methotrexate: a nonsurgical treatment alternative in tubal pregnancy].
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Data Interpretation, Statistical↗
Biomedical subjects
S Leodolter
Publications and source records attributed to S Leodolter.
Systemic methotrexate treatment of interstitial pregnancy--magnetic resonance imaging (MRI) as a valuable tool for monitoring treatment.
OBJECTIVE: Interstitial pregnancy occurs in 2-4% of ectopic pregnancies and is defined as implantation of the trophoblast in the interstitial part of the tuba uterina. Therefore the term intramural pregnancy can also be found in the literature. In 20% of the cases that progress beyond 12 weeks of amenorrhea a potentially life-threatening rupture of the uterus occurs, leading to a maternal mortality rate of 2.5%. According to the literature until a few years ago diagnosis was mainly made intraoperatively, and resulted in cornual resection or hysterectomy per laparotomy. Better methods of diagnosis and treatment of interstitial pregnancy can help to decrease morbidity and mortality associated with this condition. PATIENTS: We describe two cases of interstitial pregnancies that were eventually diagnosed and also monitored by magnetic resonance imaging (MRI) after systemic methotrexate treatment. Both patients were uniparous and experienced their second spontaneous pregnancy. METHODS: Treatment consisted of four doses (50 mg/m2 body surface area) of systemic intramuscular methotrexate alternating with four doses (6 mg) of intramuscular folic acid. When beta-hCG levels were undetectable, MRI results were compared with pre-therapeutic MRI findings. RESULTS: In patients A and B, beta-hCG levels were undetectable 64 and 88 days after initiation of methotrexate treatment, while magnetic resonance imaging revealed nearly equally persisting interstitial pregnancies. They initially presented as hyperintense lesions with hypointense zones and changed into a hypointense lesion with a central hyperintense area for patient A, and a completely hyperintense lesion for patient B at the time of negative beta-hCG levels in follow-up MRI. CONCLUSION: Systemic methotrexate treatment with an intramuscular regimen is effective in the treatment of interstitial pregnancy. MRI has the ability of correct tissue differentiation and objective three-dimensional measuring of interstitial pregnancy. We therefore propose this imaging modality as a valuable tool for monitoring systemic methotrexate treatment of interstitial pregnancy that should be used additionally to beta-hCG clearance curves.
Adult↗
p53-dependent radioresistance in ovarian carcinoma cell lines.
In the present study, we investigated the radiosensitivity profiles of three established human ovarian carcinoma cell lines, PA-1, Caov-3, and SK-OV-3, using the adenosine triphosphate-cell viability assay (ATP-CVA). We have correlated radioresponsiveness with the p53 status and the p53 accumulation after irradiation as well as with the Bcl-2 expression and the growth rate of these cell lines. The p53 status was examined by immunocytochemistry and a functional assay (functional analysis of separated alleles in yeast, FASAY); the p53 accumulation was determined by immunocytochemistry and flow cytometry. Furthermore, the Bcl-2 expression before and after irradiation was examined by immunocytochemistry. PA-1, expressing wild-type p53, showed an unequivocal accumulation of p53 protein following exposure to irradiation. This cell line was found to be strongly sensitive to irradiation. The two p53 mutant cell lines Caov-3 and SK-OV-3 showed radioresistance at different degrees and irradiation did not result in p53 accumulation. None of the cell lines examined expressed Bcl-2 protein and no change was seen after irradiation. Furthermore, the most sensitive cell line to irradiation, PA-1, showed the highest proliferative activity, while Caov-3 and SK-OV-3, the more resistant cell lines, exhibited lower growth rates. Our findings indicate that the presence of p53 protein is a possible determinant for the cytotoxicity induced by irradiation in the investigated ovarian carcinoma cell lines. Bcl-2 expression does not seem to determine the response to irradiation in these cell lines. Additionally, an association between radioresponsiveness and the growth rate is suggested in PA-1, Caov-3, and SK-OV-3.
Dose-Response Relationship, Radiation↗
Serum homocyst(e)ine levels in women with preeclampsia.
BACKGROUND: Endothelial dysfunction has been described as the final common pathophysiological pathway in the development of preeclampsia. Since it has been suggested that homocyst(e)ine damages endothelial cells, we measured serum homocyst(e)ine levels in women with preeclampsia and in healthy pregnant women in order to find a new prognostic parameter for women with preeclampsia. METHODS: Forty-five women with preeclampsia and 45 healthy women with uncomplicated pregnancies, matched for age and parity, were entered into the study. Serum homocyst(e)ine levels were measured by gas chromatography-mass spectrometry analysis and correlated to clinical data. Logistic regression models were used to analyse the influence of serum homocyst(e)ine levels on the presence of preeclampsia versus healthy pregnant women and on the risk of premature termination of pregnancy due to preeclampsia. RESULTS: Median serum homocyst(e)ine levels in women with preeclampsia and healthy pregnant women were 14.2 (range 5.7-38.1) mumol/L and 15.1 (range 5.2-23.1) mumol/L, respectively (Mann-Whitney U-test, p = 0.8). In univariate logistic regression models, serum homocyst(e)ine levels had no significant influence on the odds of presenting with preeclampsia versus healthy pregnant women (univariate logistic regression model, p = 0.8) and on the odds of premature termination of pregnancy due to preeclampsia (univariate logistic regression model, p = 0.3). CONCLUSIONS: Serum homocyst(e)ine levels are not elevated in women with preeclampsia and are not associated with clinical outcome in women with preeclampsia.
Adult↗
Could we treat more unruptured ectopic pregnancies with intramuscular methotrexate?
The main reason for the restricted use of methotrexate in the treatment of ectopic pregnancy (EP) obviously is the fear of tubal rupture in patients with lower abdominal pain after the administration of methotrexate. Therefore, we wanted to find out if patient characteristics at first presentation, such as age, pretreatment beta-hCG level, adnexal mass as visualized by transvaginal ultrasonography, or history of prior EP, would identify patients at risk for tubal rupture if they were hemodynamically stable and showed no signs of peritoneal irritation. We examined whether more patients could have been treated medically with methotrexate, because tubal rupture was unforeseeable at first presentation and inclusion criteria for methotrexate treatment were fulfilled. From January 1996 to August 1998, 122 patients diagnosed as having EP were treated at the Gynecologic Department of the University Hospital of Vienna. Inclusion criteria for medical treatment with intramuscular methotrexate (50 mg/ m(2) body surface area) were (1) hemodynamic stability, (2) an unruptured ectopic mass < or = 5 cm at the greatest dimension demonstrated at transvaginal ultrasonography; (3) beta-hCG level < or = 5,000 mIU/ml; (4) no cardiac activity of the extrauterine embryo; (5) wish of future fertility, and (6) informed consent. Patients with hemodynamic instability, severe abdominal pain, an ectopic mass > or = 5 cm at the greatest dimension, beta-hCG levels > or = 5,000 mIU/ml, cardiac activity of the extrauterine embryo, and no wish of future fertility, or disagreement with methotrexate treatment, primarily underwent surgery. Despite the fact that none of the above patient characteristics at first presentation identified patients at risk for tubal rupture, only 60/122 patients (49%) actually underwent medical treatment whereas our inclusion criteria would have granted medical treatment in 101/122 patients (83%). We determined the actual and maximal possible percentages of patients with unruptured EP eligible for medical treatment of EP with intramuscular single-dose methotrexate 50 mg/m(2) body surface area. Our data show that tubal rupture in hemodynamically stable patients is not foreseeable and should not lead to a restricted use of medical treatment in patients preferring methotrexate.
Adult↗
Accuracy of intraoperative frozen-section diagnosis in stage I endometrial adenocarcinoma.
The purpose of our study was to determine if frozen-section diagnosis accurately identified patients suffering from endometrial adenocarcinoma FIGO stage I for surgical staging consisting of total abdominal hysterectomy, bilateral salpingo-oophorectomy, peritoneal cytology, and complete bilateral pelvic lymphadenectomy in moderately differentiated tumors with myometrial invasion. In all poorly differentiated tumors, and in all tumors with deep myometrial invasion (more than 50%) surgical staging included additional para-aortic lymphadenectomy. We performed a retrospective study including 70 patients. Frozen-section diagnosis of myometrial invasion and tumor grade was compared with permanent-section diagnosis. The accuracy rates were determined, and compared with accuracy rates of frozen-section diagnosis in the literature, and a total accuracy rate for 624 patients suffering from stage I endometrial adenocarcinoma was evaluated. In our patient collective, the overall accuracy rate of frozen-section diagnosis for myometrial invasion and tumor grade was 80 and 84%, respectively. In the five comparable studies, the mean accuracy rate for myometrial invasion and tumor grade was 89 and 84%, respectively. In combination with the five comparable studies our recent study produced an accuracy rate of frozen-section diagnosis for myometrial invasion and tumor grade of 88 and 84% in 624 patients, respectively. Despite an accuracy level of frozen-section diagnosis for myometrial invasion of 80 and 84% for tumor grade in our patient collective, all patients who required surgical staging were accurately identified.
Adenocarcinoma↗
Detection of p53 polymorphism at codon 72 by PCR and allele-specific oligonucleotide hybridization on microtiter plates.
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Adult↗
Trends in vulvar neoplasia. Increasing incidence of vulvar intraepithelial neoplasia and squamous cell carcinoma of the vulva in young women.
OBJECTIVE: To determine trends in the epidemiology of vulvar intraepithelial neoplasia (VIN) and squamous cell carcinoma (SCC) of the vulva in a Central European sample during the last decade. STUDY DESIGN: A total of 366 women with VIN 2 and 3 (n = 128) or vulvar SCC (n = 238) presented within two four-year periods separated by one decade (1985-1988 and 1994-1997). We performed a retrospective analysis of the clinicopathologic records of the cohorts. RESULTS: The number of women with high grade VIN (n = 29 vs. 99) tripled during the last decade, while the incidence of vulvar SCC remained stable. In women < or = 50 years old, the incidence of high grade VIN increased by 392% (n = 12 vs. 59) and of invasive vulvar cancer by 157% (n = 7 vs. 18). In the earlier cohort there were 7/126 (5%) women with invasive vulvar SCC under the age of 50 and, in the latter cohort, 18/112 (16%, P < .01). CONCLUSION: Over the past decade a striking increase occurred in the incidence of VIN and an increase in invasive vulvar SCC in young women.
Adult↗
Expression of mucins and cytokeratins in ovarian cancer cell lines.
The expression pattern of the epithelial cell markers MUC1 (CA15-3, EMA), CA125 (OC125), human epithelial antigen HEA (Ber-EP4) and cytokeratins (Ck7, Ck8, Ck7/8, Ck8/18/19) was studied in seven human ovarian cancer cell lines. We analyzed the cell lines by immunofluorescence to determine the surface as well as cytoplasmic expression. Furthermore, we evaluated the mRNA expression of MUC1, Ck18 and Ck19 by reverse transcriptase-polymerase chain reaction (RT-PCR). All cell lines were positive for MUC1. However, expression patterns and staining intensity depended on the different epitope-specific antibodies. CA125, a typical serum marker for ovarian carcinomas, was positive only in two cell lines. HEA was strongly positive in three cell lines, whereas the others expressed the antigen only weakly in the cytoplasm. Ck7 was not expressed in three of the seven cell lines. Ck7/8 was detectable in all cell lines and was strongly expressed in four of them. MUC1 mRNA was expressed by all cell lines as detected by RT-PCR. These findings permit selection of a suitable marker for the detection of disseminated ovarian cancer cells.
Antigens, Neoplasm↗
Serum concentrations of squamous-cell carcinoma antigen and tissue polypeptide antigen in the follow-up of patients with vulvar cancer.
Our aim was to evaluate the clinical usefulness of serum concentrations of squamous-cell carcinoma antigen (SCC-Ag) and tissue polypeptide antigen (TPA) in the follow-up of patients with vulvar cancer. We measured SCC-Ag and TPA in 480 serum samples of 82 patients with squamous-cell vulvar cancer. Results were correlated with clinical data. SCC-Ag, TPA and the combination of SCC-Ag and TPA reached a sensitivity and specificity of 27%/97%, 28%/75% and 40%/73%, respectively. The sensitivity and specificity of the marker combination SCC-Ag and TPA was not significantly higher compared with SCC-Ag alone (McNemar's test, p = 0.6 and p = 0.09, respectively). Of the 35 patients with recurrent disease during follow-up, 19, 6 and 10 developed local, regional and distant recurrent disease, respectively. SCC-Ag showed lead-time effects in 26%, 75% and 50% and TPA in 25%, 0% and 33% of patients with local, regional and distant recurrent disease, respectively. The combination of SCC-Ag and TPA showed lead-time effects in 50%, 75% and 50% of patients with local, regional and distant recurrent disease, respectively. The difference between median lead-times of the combination of SCC-Ag and TPA and SCC-Ag alone was not statistically significant (Mann-Whitney U-test, p = 0.4). Our data show that serum SCC-Ag displays good sensitivity/specificity characteristics in the follow-up of vulvar cancer patients, with lead-time effects seen in 75% and 50% of patients with regional and distant recurrent disease, respectively. Furthermore, our data indicate that combining SCC-Ag with TPA is not a successful strategy to improve the sensitivity or the duration of lead-time effects in the follow-up of patients with vulvar cancer.
Adult↗
Serum concentrations of squamous cell carcinoma antigen in patients with vulvar intraepithelial neoplasia and vulvar cancer.
Our aim was to evaluate whether serum concentrations of squamous cell carcinoma antigen (SCC-Ag) are an independent prognostic factor in patients with vulvar cancer. We measured SCC-Ag in pretreatment serum samples of 55 patients with squamous cell vulvar cancer, 30 patients with vulvar intraepithelial neoplasia (VIN) grade III and 50 healthy female controls. The results were compared with clinical data. Median serum concentrations of SCC-Ag in healthy female controls, patients with VIN III, and patients with invasive vulvar cancer were 0.5 (range 0.1 to 3.8) ng/mL, 0.5 (range 0 to 4.1) ng/mL and 1.6 (range 0.3 to 65) ng/mL, respectively (Mann-Whitney U test, p < 0.001). The 75% quantile of serum concentrations of SCC-Ag in patients with vulvar cancer was defined as cut-off level. Elevated pretreatment serum concentrations of SCC-Ag were significantly correlated with a shorter disease-free and overall survival (log-rank test, p=0.002; and p<0.001, respectively). A multivariate Cox regression model showed that serum concentrations of SCC-Ag are a prognostic factor of disease-free and overall survival independent of tumour stage (multivariate Cox regression model, p=0.03; and p=0.048, respectively). Pre-treatment serum concentrations of SCC-Ag were not correlated with tumour stage, histological grade and patients' age. In summary, our data indicate that serum concentrations of SCC-Ag may be an additional independent prognostic factor of disease-free and overall survival in patients with vulvar cancer.
Adult↗
Prognostic significance of tumor angiogenesis in epithelial ovarian cancer.
Since angiogenesis is considered essential for tumor growth and the development of metastasis, we assessed the correlation of microvessel density (MVD) with overall survival in patients with epithelial ovarian cancer. Histologic slides were immunostained for CD34-antigen. MVD was determined within each tumor by enumeration under a light microscope at 200x magnification and an examination area of 0.25 mm2. The Cox proportional-hazards model was used for multivariate analysis. In 63 patients with epithelial ovarian cancer the 5-year survival rate (OS-%) was as follows: 55.0% (+/-12.5) in 18 patients whose tumors had an MVD < 10/field, and 23.6% (+/-6.7) in 45 patients whose tumors had an MVD(10/field (log-rank P = 0.038). MVD showed a significant influence on survival in univariate analysis, but failed to attain a significant value after adjustment for established prognostic parameters such as patients' age at diagnosis, stage of disease, and histologic grading. High MVD was significantly associated with advanced patients' age at diagnosis. This and a considerable heterogenity in the vascular architecture of ovarian carcinoma tissue might be the reasons why MVD did not reveal prognostic significance in multivariate analysis. In contrast to a variety of solid neoplasms, MVD does not seem to be a useful predictor of survival in patients with epithelial ovarian cancer.
Adult↗
[Angiogenesis in gynecology and obstetrics].
In current scientific discussion, increasing importance is being given to the clinical significance of the new formation of vessels (angiogenesis) in the course of physiological, inflammatory and neoplastic processes. Angiogenesis is best studied in the growth of malignant tumors, since cancer may be regarded as the most important angiogenesis-dependent disease in terms of social and economic aspects. The significance of angiogenesis in gynecological oncology is as follows: 1) Intratumoral vessel density is an indicator for the emergence and growth of malignant tumours and their precursor lesions, 2) intratumoral vessel density is an independent prognostic factor for solid malignancies and 3) the inhibition of tumor angiogenesis by means of anti-angiogenetic substances causes tumor growth to be suppressed. Angiogenesis also plays an important role in the regulation of the female menstrual cycle. Proliferation of the endometrium and the formation of the corpus luteum in the second half of the menstrual cycle are examples of angiogenesis in the physiological field. The function of angiogenetic factors in the emergence of endometriosis and in female and male infertility are currently under study. In obstetrics, the new formation of blood vessels is significant for the implantation of impregnated blastocysts and for the development and growth of the placenta. Preeclempsia (gestational toxicosis), for instance, is a typical pregnancy-related disease whose pathophysiological mechanism is attributed to a disturbed development and function of small placental vessels. The present paper is an overview of current knowledge and current approaches of research concerning angiogenesis in the field of gynecology and obstetrics. The paper is focused on the clinical significance of angiogenesis.
Angiogenesis Inducing Agents↗
Leiomyosarcoma of the uterus: a clinicopathologic multicenter study of 71 cases.
OBJECTIVE: The aim of this study was to evaluate the behavior of uterine leiomyosarcomas in relation to their clinical and pathologic features and to identify possible prognostic factors. METHODS: Seventy-one patients with histologically proven uterine leiomyosarcoma were included in the analysis. Leiomyosarcomas were defined as uterine smooth-muscle tumors with five or more mitoses per 10 high-power fields and cytologic atypia. Cox proportional hazards regression model was used to identify independent prognostic factors. RESULTS: The median follow-up time was 108 months; 5-year overall survival rate was 65%. Evaluating the correlation between several clinicopathologic parameters, tumors with vascular space involvement had a statistically significantly higher stage than tumors without vasular space involvement (P = 0.015). In a univariate Cox model early tumor stage (P < 0.0001), age <50 years (P < 0.0001), low mitotic count (P = 0.05), and the absence of vascular space involvement (P < 0.0005) were associated with good prognosis. In a multivariate analysis age (P = 0.002), tumor stage (P = 0.004), vascular space involvement (P = 0.003), and mitotic count in stage I tumors (P = 0.002) were found to be independent parameters for good prognosis in patients with uterine leiomyosarcoma. CONCLUSION: Early tumor stage, age <50 years, and absence of vascular space involvement were independently associated with good prognosis. Mitotic count was detected to be a strong prognostic parameter in early tumor stage, but failed to act as an independent prognostic parameter in patients with tumor stage II-IV disease.
Adult↗
Vascular endothelial growth factor and its receptors in male fertility.
OBJECTIVE: To determine the concentration of vascular endothelial growth factor in the seminal fluid, the presence of vascular endothelial growth factor receptors Flt-1 and KDR in spermatozoa, and the predictive value of seminal vascular endothelial growth factor on fertilization and the chance of pregnancy in patients undergoing intracytoplasmic sperm injection (ICSI) or IVF. DESIGN: Retrospective analysis. SETTING: Private institute (semen collection, IVF/ICSI) and academic research environment (analysis of seminal fluid and spermatozoa). PATIENT(S): Eighty men whose spermatozoa were subsequently used for IVF or ICSI. INTERVENTION(S): Seminal vascular endothelial growth factor was measured by an EIA. Spermatozoa were analyzed by fluorescence-activated cell sorter analysis and by immunocytochemistry. MAIN OUTCOME MEASURE(S): Oocyte fertilization rate, pregnancy rate, and presence of vascular endothelial growth factor receptors on spermatozoa. RESULT(S): Patients with a seminal concentration of vascular endothelial growth factor of 2-100 ng/mL had a sixfold increased chance of pregnancy. Vascular endothelial growth factor concentration and patient's age remained the only independent prognostic factors for pregnancy. The concentration of vascular endothelial growth factor did not correlate with indices of male factor infertility or with the oocyte fertilization rate. Expression of vascular endothelial growth factor receptors (Flt-1, KDR) on spermatozoa was demonstrated. CONCLUSION(S): The seminal concentration of vascular endothelial growth factor correlates with the chance of pregnancy in patients undergoing IVF or ICSI. Vascular endothelial growth factor receptors Flt-1 and KDR were detected on spermatozoa for the first time.
Adult↗
Association between endometrial cancer and tamoxifen treatment of breast cancer.
A retrospective cohort-study in 4109 breast cancer patients was undertaken to determine how tamoxifen affected the risk of endometrial cancer. Data on 1701 tamoxifen-treated women were analysed. Two thousand four hundred and eight non-tamoxifen users served as control group. The occurrence of new primary uterine cancers was assessed by computerized linkage to the Austrian Cancer Registry. Twenty-five women who subsequently developed endometrial cancer were identified. Eight uterine cancers occurred in the tamoxifen group, whereas 17 uterine cancers were found in the control group. The estimate of the relative risk (RR) showed an increased risk to develop endometrial cancer for the tamoxifen group RR 1.136 (95% CI 0.71; 1.80). Analysis of relevant confounding variables did not show any differences in the two groups. In conclusion, this retrospective study demonstrated a non-significant increased risk of endometrial cancer in women receiving tamoxifen as treatment for breast cancer. However, the magnitude of RR and the absolute number of endometrial cancer cases in this long term observation demonstrate clearly that the clinical benefit of tamoxifen therapy greatly outweighs the risk.
Breast Neoplasms↗
Tumor flow in malignant breast tumors measured by Doppler ultrasound: an independent predictor of survival.
The purpose of this study was to investigate tumor blood flow in breast cancers with regard to its impact on the overall survival of patients. Tumor blood flow was assessed in seventy-four patients with primary breast cancer by the use of color-coded Doppler ultrasound techniques. Preoperatively obtained Doppler frequency spectra were analyzed for peak systolic flow velocity (Vmax). Color Doppler signals were detected in 71 (96%) of the breast tumors. Out of 74 patients, 17 experienced a relapse or distant metastasis, and 15 women had died due to breast cancer at the time of data analysis. The mean Vmax of the patients who had died was 0.27 m s(-1), whereas survivors showed a mean Vmax of 0.16 m s(-1) (p = 0.01). Vmax, nodal status, and progesterone receptor status remained the only significant factors of overall survival in the multivariate model, whereas tumor size, tumor grade, and estrogen receptor status failed to retain prognostic significance. Moreover, Vmax was identified as the most important prognostic marker for survival in our series. The five-year-survival was 82.3% in Vmax < or = 0.25 m s(-1) patients versus 36.6% in women with tumor flow greater than 0.25 m s(-1). Patients with Vmax > 0.25 m s(-1) experienced a 4.33-fold increased risk of death secondary to the underlying disease. In summary, our data showed that tumor blood flow velocity measured by ultrasonography is an independent prognostic factor of survival in breast cancer patients. Furthermore, tumor flow velocity allows identification of patients at very high risk of death due to breast cancer. Large scale clinical trials should evaluate the clinical usefulness and future impact of this procedure for adjuvant treatment decisions.
Adult↗
Association of in vitro invasiveness and gene expression of estrogen receptor, progesterone receptor, pS2 and plasminogen activator inhibitor-1 in human breast cancer cell lines.
The invasive potential of tumor cells is usually tested either by in vitro invasion assays which evaluate cell spreading ability in basement membrane-like matrices or by in vivo invasion assays in nude mice. Both methods are laborious and time-consuming. Tumor invasiveness is accompanied by the changes in expression of various genes. The invasive behavior of cells is therefore represented by certain gene expression patterns. The purpose of this study was to investigate whether expression patterns of several genes are characteristic for the invasiveness of cultured cells. We examined the mRNA levels of estrogen receptor (ER), progesterone receptor (PR), estrogen inducible pS2 and plasminogen activator inhibitor-1 (PAI-1) in 23 cell lines derived from benign and malignant breast tissues using a competitive reverse transcription-polymerase chain reaction (cRT-PCR) system. We also evaluated the invasiveness of these cell lines by their ability to penetrate into a collagen-fibroblast matrix. We demonstrate that the gene expression pattern of breast cell lines is clearly associated with their in vitro invasiveness. In general, cells with ER, PR, pS2 but no PAI-1 expression showed a non-invasive phenotype, while cells expressing PAI-1 mRNA but not ER mRNA are invasive. Our study indicates that the invasiveness of breast cancer cell lines is characterized by PAI-1 gene expression and the lack of ER mRNA. This suggests that PAI-1 may participate in the invasive process.
Biomarkers, Tumor↗