Methotrexate or expectant management in women with an ectopic pregnancy or pregnancy of unknown location and low serum hCG concentrations? A randomized comparison.

STUDY QUESTION: What is the treatment success rate of systemic methotrexate (MTX) compared with expectant management in women with an ectopic pregnancy or a pregnancy of unknown location (PUL) with low and plateauing serum hCG concentrations? SUMMARY ANSWER: In women with an ectopic pregnancy or a PUL and low and plateauing serum hCG concentrations, expectant management is an alternative to medical treatment with single-dose systemic MTX. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: MTX is often used in asymptomatic women with an ectopic pregnancy or a PUL with low and plateauing serum hCG concentrations. These pregnancies may be self-limiting and watchful waiting is suggested as an alternative, but evidence from RCTs is lacking. The results of this RCT show that expectant management is an alternative to treatment with systemic MTX in a single-dose regimen in these women. STUDY DESIGN, SIZE, DURATION: A multicentre RCT women were assigned to systemic MTX (single dose) treatment or expectant management, using a web-based randomization program, block randomization with stratification for hospital and serum hCG concentration (<1000 versus 1000-2000 IU/l). The primary outcome measure was an uneventful decline of serum hCG to an undetectable level (<2 IU/l) by the initial intervention strategy. Secondary outcome measures included additional treatment, side effects and serum hCG clearance time. PARTICIPANTS, SETTING, METHODS: From April 2007 to January 2012, we performed a multicentre study in The Netherlands. All haemodynamically stable women >18 years old with both an ectopic pregnancy visible on transvaginal sonography and a plateauing serum hCG concentration <1500 IU/l or with a PUL and a plateauing serum hCG concentration <2000 IU/l were eligible for the trial. MAIN RESULTS: We included 73 women of whom 41 were allocated to single-dose MTX and 32 to expectant management. There was no difference in primary treatment success rate of single-dose MTX versus expectant management, 31/41 (76%) and 19/32 (59%), respectively [relative risk (RR) 1.3 95% confidence interval (CI) 0.9-1.8]. In nine women (22%), additional MTX injections were needed, compared with nine women (28%) in whom systemic MTX was administered after initial expectant management (RR 0.8; 95% CI 0.4-1.7). One woman (2%) from the MTX group underwent surgery compared with four women (13%) in the expectant management group (RR 0.2; 95% CI 0.02-1.7), all after experiencing abdominal pain within the first week of follow-up. In the MTX group, nine women reported side effects versus none in the expectant management group. No serious adverse events were reported. Single-dose systemic MTX does not have a larger treatment effect compared with expectant management in women with an ectopic pregnancy or a PUL and low and plateauing serum hCG concentrations. WIDER IMPLICATIONS OF THE FINDINGS: Sixty percent of women after expectant management had an uneventful clinical course with steadily declining serum hCG levels without any intervention, which means that MTX, a potentially harmful drug, can be withheld in these women. BIAS, LIMITATION AND GENERALISABILITY: A limitation of this RCT is that it was an open (not placebo controlled) trial. Nevertheless, introduction of bias was probably limited by the strict criteria to be fulfilled for treatment with MTX. STUDY FUNDING: This trial is supported by a grant of the Netherlands Organization for Health Research and Development (ZonMw Clinical fellow grant 90700154). TRIAL REGISTRATION: ISRCTN 48210491.

Gonadotropins and female sex steroid hormones in cyst fluid and serum from patients with ovarian tumors.

The objective of the present study was to determine the concentrations of LH, FSH, 17beta-estradiol and progesterone in ovarian cyst fluid and serum from patients with benign and malignant ovarian tumors and to assess the correlation of the gonadotropin and female sex steroid hormone concentrations with menopausal and tumor status. Ovarian cyst fluid and blood samples were prospectively collected from 103 patients with ovarian tumors. Seventy-four of the patients had benign ovarian tumors while 29 patients had malignant ovarian tumors. Malignant ovarian tumors showed significantly higher LH and FSH cyst fluid concentrations compared to concentrations from patients with benign tumors. Within the malignant subset, LH and FSH concentrations correlated with increasing FIGO stage and grade. Furthermore, LH and FSH cyst fluid concentrations showed strong correlations (r > 0.62) with serum concentrations in case of malignant tumors, especially in postmenopausal women, but not in case of benign tumors. The highest gonadotropin concentrations were observed in cyst fluid from malignant ovarian tumors. The most probable explanation for this is an increased vascular permeability within the cysts. Supportive evidence for such an increased vascular permeability is our previous finding of significantly higher VEGF concentrations in cyst fluid from malignant ovarian tumors. The possibility of ectopic production of LH and FSH by malignant ovarian tissue cannot completely be ruled out.

Pregnancy after radical trachelectomy: a real option?

INTRODUCTION: Radical trachelectomy is a surgical procedure for early-stage cervical carcinoma with preservation of the childbearing capacity. The current article presents a review of studies describing the results and complications of pregnancies after this procedure. METHODS: Sixteen studies were included (involving 355 radical trachelectomy procedures). Studies were reviewed for the number of patients included, the number attempting to conceive, the number who achieved pregnancy, the number of pregnancies achieved, the numbers of first and second trimester losses, and when delivery occurred in the third trimester. RESULTS: One hundred and fifty-three patients attempted to conceive during the follow-up period (range 1-144 months), this accounts for 43% of the patients that underwent radical trachelectomy. 70% of the patients attempting to conceive succeeded once or more than once. 161 pregnancies were described, finally resulting in 49% term deliveries. In about 15% of the patients who tried to conceive, cervical stenosis was found and resulted in menstrual disorders or fertility problems. Surgical dilatation resolved this problem in most cases but had to be repeated. Complications during pregnancy involved second trimester loss (13/161) and premature (< or =36 weeks AD) delivery (33/161). CONCLUSIONS: Pregnancy after radical trachelectomy is feasible. For various reasons, a number of patients (57%) did not try to get pregnant after the surgical procedure. The majority of the patients who tried to conceive after radical trachelectomy succeeded once or more than once (70%). Patients attempting to conceive need to be informed of the complications and risk factors, in particular, second trimester loss and premature delivery caused by premature rupture of membranes. Once pregnant, patients need to be carefully followed for cervical incompetence and other risk factors for premature rupture of membranes.

Clinical value of components of the plasminogen activation system in ovarian cyst fluid.

BACKGROUND: The aim of this study was to analyze the concentrations of different components of the plasminogen activation system in cyst fluid from malignant, borderline and benign ovarian tumors and to compare these results with clinicopathological characteristics (FIGO staging, histological grading, residual tumor, ascites, tumor recurrence and disease-free survival). MATERIALS AND METHODS: One hundred and seven cyst fluid samples were enrolled from 25 malignant, 12 borderline and 70 benign ovarian tumors. Determination of uPA, tPA, PAI-1, PAI-2, uPA:PAI-1 complex and tPA:PAI-1 complex was performed by specific double determinant ELISAs based on the concept described previously by Grebenschikov et al. With these ELISAs both complexes of the activators (uPA, tPA) with their inhibitor (PAI-1) can be measured as a separate component. RESULTS: Significant differences were found in median cyst fluid concentrations of uPA, PAI-1, uPA:PAI-1 and tPA:PAI-1 from malignant, borderline and benign ovarian tumors, with the highest levels in malignant ovarian tumors. Cystic endometriosis seems to be a special entity within the benign subclass. To achieve better discrimination between malignant and benign cases we introduced a new malignancy index: ([uPA:PAI-1]+[tPA:PAI-1])x [PAI-1]. The area under a Receiver Operating Characteristic (ROC) curve amounted to 0.80. Significantly higher concentrations were found in FIGO stages II-III-IV compared with stage I for uPA (p<0.05), tPA (p<0.05), uPA:PAI-1 (p<0.01) and tPA:PAI-1 (p<0.05). CONCLUSION: Concentrations of plasminogen activation system markers in cyst fluid from ovarian tumors are related to histological subtype. The most significant components are uPA, PAI-1 and the complexes uPA:PAI-1, tPA:PAI-1. The prognostic value of the components seems to be limited but might be important in detecting high-risk borderline or low stage patients.

Post-radiotherapy contrast enhancement changes in fast dynamic MRI of cervical carcinoma.

This pilot study determines fast dynamic gadolinium enhanced MRI contrast enhancement parameters (onset of enhancement and time to peak enhancement) before and after radiotherapy in 10 cervical carcinoma patients. Before radiotherapy, onset of enhancement and time to peak enhancement were early, with a median of 4.5 and 5.2 seconds, respectively. High-grade tumors showed early enhancement, compared with low-grade. After radiotherapy, contrast enhancement patterns differed. In survivors, onset of enhancement after radiotherapy was later than before radiotherapy. In non-survivors, onset of enhancement after radiotherapy was still early. The median difference in onset of enhancement before and after radiotherapy in survivors and non-survivors was an increase of 3.2 and a decrease of 1.1 seconds, respectively. Early onset of enhancement after radiotherapy was a better predictor for survival than a high-signal intensity zone on post radiotherapy unenhanced T1/T2-weighted MRI. It is concluded that enhancement parameters from fast dynamic Gd-enhanced MR images can provide additional functional information with regard to tumor vascularization, and may have prognostic significance. It complements clinical examination and unenhanced MRI in determining the effectiveness of radiotherapy treatment in cervical carcinoma. Future studies will focus on the clinical utility and improvements of the estimation of contrast-enhanced parameters with this new technique.

Vascular endothelial growth factor in ovarian cyst fluid.

BACKGROUND: The purpose of the current study was to determine vascular endothelial growth factor (VEGF) concentrations in cyst fluid from malignant, borderline, and benign ovarian tumors, and to correlate these data with preoperative serum VEGF concentrations and clinicopathologic characteristics. METHODS: One hundred seven ovarian cysts were removed and punctured for cyst fluid collection. Histologic diagnosis revealed 25 malignant, 12 borderline, and 70 benign ovarian tumors. The VEGF concentrations of all the cyst fluid specimens as well as in 37 preoperatively collected serum samples were determined by making use of a sandwich type double determinant enzyme linked immunoadsorbent assay based on a combination of 4 polyclonal antibodies. RESULTS: Statistically significantly higher VEGF concentrations were found in cyst fluid from malignant (median, 21.5 microg/L) compared with borderline (median, 3.2 microg/L; P = 0.01) or benign tumors (median, 1.3 microg/L; P < 0.0001). Preoperative serum VEGF concentrations were significantly higher in patients with malignant (median, 0.63 microg/L; range, 0.016-17.7 microg/L) compared with nonmalignant tumors (median, 0.28 microg/L; range, 0.016-0.89 microg/L; P = 0.008). A significant correlation of preoperative serum VEGF was found with VEGF cyst fluid concentrations (r = 0.38; P = 0.02). Significantly higher VEGF cyst fluid concentrations were found in serous malignant (median, 31.9 microg/L) compared with mucinous malignant tumors (median, 4.7 microg/L; P = 0.004). Not significant, though higher median VEGF cyst fluid concentrations were found in advanced International Federation of Gynecology and Obstetrics (FIGO) Stage II, III, and IV, histologic Grade 2 and 3, patients with residual tumor greater than 2 cm, with malignant cells in ascites or peritoneal washings, or with recurrent disease, as compared with FIGO Stage I, histologic grade 1, patients with less than or equal to 2-cm residual tumor, without malignant cells in ascites/peritoneal washings, or without recurrent disease, respectively. CONCLUSIONS: It has become clear from the increased study sample that ovarian tumors of different histologic etiology vary in VEGF cyst fluid concentrations, with the highest VEGF cyst fluid concentrations in malignant tumors. The prognostic significance of VEGF cyst fluid concentrations in advanced FIGO stage seems to be of limited value but may be important in the selection of high risk FIGO Stage I and borderline types. Data from this study indicate a possible role for VEGF as a serum tumor marker.

Glutathione S-transferases P1-1 and A1-1 in ovarian cyst fluids.

PURPOSE: The purpose of the present study was to determine the gluthathione S-transferases (GST) P1-1 and A1-1 levels in cyst fluid from malignant, borderline, and benign ovarian tumors. The clinical relevance of these enzymes in cyst fluid was investigated, including the possible relation with resistance to chemotherapy. METHODS: A total of 90 ovarian cysts were punctured for cyst fluid collection. GSTP1-1 and GSTA1-1 concentrations were determined by ELISA in cyst fluid from 23 malignant, 9 borderline, and 51 benign primary ovarian tumors, and levels were correlated with histopathological data. RESULTS: Significantly higher GSTP1-I concentrations were found in cyst fluid from malignant (median: 477 ng/ml), compared with benign (median: 52 ng/ml) ovarian cysts (p < 0.0001), as well as in fluid from borderline (median: 366 ng/ml) compared with benign cysts (p < 0.0001). No significant differences were found in cyst fluid GSTA1-1 concentrations between the histologic subgroups. In cyst fluid from malignant tumors higher GSTPI-1 and lower GSTAI-1 concentrations were found in patients with worse prognostic factors: FIGO II-III-IV, grade 2-3, residual tumor > 2 cm, presence of ascites, patients with recurrent disease, and survival, but differences were not significant. In the subgroup of patients that received cisplatin-based chemotherapy (n = 14) significantly higher GSTP1-1 (p = 0.01) concentrations were found in patients with recurrence compared with patients without recurrence. Considering only FIGO stage I patients, a differentiation could be made between patients with or without recurrence based on cyst fluid GSTP I - I concentrations. CONCLUSIONS: Determination of glutathione S-transferases P 1-1 in cyst fluid samples from ovarian tumors can be of additiona] value in the differentiation between histologic subgroups. In case of possible low malignant potential cysts where sampling of the most representative tissue can be an issue, determination of GSTP- I concentrations in cyst fluid may optimise histopathologic classification. Cyst fluid GSTP1-1 seems to be a good marker for aggressiveness of the ovarian tumor, and it may predict response to chemotherapy.

High-resolution proton nuclear magnetic resonance spectroscopy of ovarian cyst fluid.

Most ovarian tumors are cystic structures containing variable amounts of fluid. Several studies of ovarian cyst fluid focus on one specific metabolite using conventional assay systems. We examined the potential of (1)H-nuclear magnetic resonance spectroscopy in evaluation of the overall metabolic composition of cyst fluid from different ovarian tumors. Ovarian cyst fluid samples obtained from 40 patients with a primary ovarian tumor (12 malignant and 28 benign) were examined. After deproteinization and pD standardization, we performed (1)H-NMR spectroscopy on a 600 MHz instrument. With (1)H-NMR spectroscopy we found detectable concentrations of 36 metabolites with high intersample variation. A number of unassigned resonances as well as unexpected metabolites were found. We introduce an overall inventory of the low-molecular-weight metabolites in ovarian cyst fluid with corresponding resonances. Significant differences in concentration (p < 0.01) were found for several metabolites (including an unknown metabolite) between malignant and benign ovarian cysts. Furthermore, higher concentrations in malignant- and lower in benign fluids were found compared to normal serum values, indicating local cyst wall metabolic processes in case of malignant transformation. We conclude that (1)H-nuclear magnetic resonance spectroscopy can give an overview of low-molecular-weight proton-containing metabolities present in ovarian cyst fluid samples. The metabolic composition of cyst fluid differs significantly between benign and malignant ovarian tumors. Furthermore, differences between benign subgroups possibly related to histopathological behaviour can be detected. The presence of N-acetyl aspartic acid and 5-oxoproline exclusively in serous cystadenoma samples is remarkable. Future studies will concentrate on these findings and explore the possibilities of extrapolating information from the in vitro studies to in vivo practice, in which metabolic differences between malignant and benign subtypes can be of great importance in a pre-operative phase.

The role of MR imaging in invasive cervical carcinoma.

In this article the role of MR imaging in the management of cervical cancer is reviewed and illustrated. The appearance of the normal uterine cervix and of cervical carcinoma is shown. Important factors for optimal MR imaging of cervical carcinoma are reviewed. The value of MR imaging in the staging of cervical carcinoma is illustrated by showing parametrial invasion and lymph node involvement. Finally, the value of MR imaging staging is compared with clinical staging, CT staging, and surgical findings. The role of new imaging techniques, such as fast dynamic enhanced MR imaging, is described.

Cytologic examination to detect clear cell adenocarcinoma of the vagina or cervix.

OBJECTIVE: The aim of this study was to determine the sensitivity of cytopathologic examination for the detection of vaginal or cervical clear cell adenocarcinoma (CCA). METHODS: Systematic collection in the Dutch automated nationwide pathology archive of all cytology and histology data of women with CCA, born in The Netherlands after 1947 was performed. All cytologic examinations within 2 years prior to histological diagnosis of CCA were included. RESULTS: Ninety patients with CCA have been registered. Forty-nine of these patients had cytologic examinations prior to histology. Eighty-five percent of cervical CCAs were preceded by a positive cervical smear. One hundred percent of vaginal CCAs were preceded by a positive vaginal smear. Cervical smears are relatively insensitive to detect vaginal CCA. Vaginal smears were often omitted. Only 2 apparently false-negative smears were found. The mean numbers of smears in diethylstilbestrol (DES)-exposed and nonexposed women were minimally different: 1.0 and 0.8, respectively. This suggests an only modest impact of the awareness of DES as a risk factor. FIGO tumor stage I was preceded more frequently by cytology than the higher tumor stages. CONCLUSION: The majority of CCA cases can be detected at an early stage by yearly clinical and cytological examinations, which must comprise cervical as well as vaginal sampling. Since CCA may also occur in postmenopausal women, for the purpose of secondary prevention of CCA regular cytologic examinations of DES-exposed women must be continued after menopause.