Erik A. Boss

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 1H‐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 1H‐NMR spectroscopy on a 600 MHz instrument. With 1H‐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 1H‐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. Copyright

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.

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. J. Magn. Reson. Imaging 2001;13:600–606.

Laparoscopy to Predict the Result of Primary Cytoreductive Surgery in Patients With Advanced Ovarian Cancer: A Randomized Controlled Trial

Purpose To investigate whether initial diagnostic laparoscopy can prevent futile primary cytoreductive surgery (PCS) by identifying patients with advanced-stage ovarian cancer in whom > 1 cm of residual disease will be left after PCS. Patients and Methods This multicenter, randomized controlled trial was undertaken within eight gynecologic cancer centers in the Netherlands. Patients with suspected advanced-stage ovarian cancer who qualified for PCS were eligible. Participating patients were randomly assigned to either laparoscopy or PCS. Laparoscopy was used to guide selection of primary treatment: either primary surgery or neoadjuvant chemotherapy followed by interval surgery. The primary outcome was futile laparotomy, defined as a PCS with residual disease of > 1 cm. Primary analyses were performed according to the intention-to-treat principle. Results Between May 2011 and February 2015, 201 participants were included, of whom 102 were assigned to diagnostic laparoscopy and 99 to primary surgery. In the laparoscopy group, 63 (62%) of 102 patients underwent PCS versus 93 (94%) of 99 patients in the primary surgery group. Futile laparotomy occurred in 10 (10%) of 102 patients in the laparoscopy group versus 39 (39%) of 99 patients in the primary surgery group (relative risk, 0.25; 95% CI, 0.13 to 0.47; P < .001). In the laparoscopy group, three (3%) of 102 patients underwent both primary and interval surgery compared with 28 (28%) of 99 patients in the primary surgery group ( P < .001). Conclusion Diagnostic laparoscopy reduced the number of futile laparotomies in patients with suspected advanced-stage ovarian cancer. In women with a plan for PCS, these data suggest that performance of diagnostic laparoscopy first is reasonable and that if cytoreduction to < 1 cm of residual disease seems feasible, to proceed with PCS.

Cost-effectiveness of laparoscopy as diagnostic tool before primary cytoreductive surgery in ovarian cancer

OBJECTIVE To evaluate the cost-effectiveness of a diagnostic laparoscopy prior to primary cytoreductive surgery to prevent futile primary cytoreductive surgery (i.e. leaving >1cm residual disease) in patients suspected of advanced stage ovarian cancer. METHODS An economic analysis was conducted alongside a randomized controlled trial in which patients suspected of advanced stage ovarian cancer who qualified for primary cytoreductive surgery were randomized to either laparoscopy or primary cytoreductive surgery. Direct medical costs from a health care perspective over a 6-month time horizon were analyzed. Health outcomes were expressed in quality-adjusted life-years (QALYs) and utility was based on patients response to the EQ-5D questionnaires. We primarily focused on direct medical costs based on Dutch standard prices. RESULTS We studied 201 patients, of whom 102 were randomized to laparoscopy and 99 to primary cytoreductive surgery. No significant difference in QALYs (utility=0.01; 95% CI 0.006 to 0.02) was observed. Laparoscopy reduced the number of futile laparotomies from 39% to 10%, while its costs were € 1400 per intervention, making the overall costs of both strategies comparable (difference € -80 per patient (95% CI -470 to 300)). Findings were consistent across various sensitivity analyses. CONCLUSION In patients with suspected advanced stage ovarian cancer, a diagnostic laparoscopy reduced the number of futile laparotomies, without increasing total direct medical health care costs, or adversely affecting complications or quality of life.

Long-term risk of endometrial cancer following postmenopausal bleeding and reassuring endometrial biopsy.

Women with postmenopausal bleeding and endometrial thickness >4 mm undergo endometrial sampling to exclude endometrial cancer. The aim of this study is to investigate the relative risk of developing endometrial cancer in a prospective cohort after initial work‐up for postmenopausal bleeding showing reassuring histology or insufficient sampling.

Long-term Risk of Endometrial Cancer Following Postmenopausal Bleeding and Reassuring Endometrial Biopsy

ABSTRACT Women with postmenopausal bleeding who present with an endometrial thickness 4 mm or less are at a very low risk of endometrial cancer, and therefore refraining from endometrial sampling in these women is considered justified. If the endometrial thickness is more than 4 mm, endometrial sampling is indicated to exclude endometrial cancer. Although women with a histological finding of endometrial hyperplasia without atypia have a slightly increased risk of developing endometrial cancer, this finding is generally regarded as a reassuring histology without the need for further follow-up. A recently published prospective cohort study reported that in 84 (29.8%) of 356 women presenting with postmenopausal bleeding and endometrial thickness of more than 4 mm, outpatient endometrial sampling failed because the amount of tissue was insufficient for a reliable histopathologic diagnosis. When endometrial sampling fails, there is currently no consensus on what to do. No long-term follow-up studies have reported the incidence of endometrial cancer after failure of endometrial sampling. The aim of this long-term cohort follow-up study was to investigate the relative risk of developing endometrial cancer after initial workup for postmenopausal bleeding shows reassuring histology or insufficient endometrial sampling. The authors hypothesized that women with postmenopausal bleeding and failure of endometrial sampling have an increased risk of endometrial (pre)malignancies. Participants were women with postmenopausal bleeding presenting at 3 hospitals in the Netherlands between January 2009 and April 2011. Long-term follow-up data were collected from the patient charts of the 3 participating hospitals and from PALGA, the Dutch Pathology Registry. Standardized incidence ratios were calculated to estimate the risk of endometrial cancer, relative to the general population. A total of 668 women presented with postmenopausal bleeding; of these, 568 were available for follow-up. Median follow-up time was 47 months (range, 7–63 months). Women with postmenopausal bleeding, endometrial thickness of more than 4 mm, and hyperplasia without atypia on biopsy at the first presentation had a 17 times increased risk of developing endometrial cancer during the first 4 years of follow-up compared with the age-specific population; the standardized incidence ratio was 17.15, with a 95% confidence interval of 1.96 to 61.93. All women who developed endometrial cancer after initial reassuring histology presented with recurrent postmenopausal bleeding. During follow-up, no endometrial cancer was diagnosed in women with endometrial thickness of more than 4 mm and no or insufficient histology at initial presentation. Despite an initial reassuring histological finding of endometrial hyperplasia without atypia, women with postmenopausal bleeding and endometrial thickness of more than 4 mm had a significantly increased risk of endometrial cancer during 4 years of follow-up compared with the age-specific population. Further studies are needed to determine whether additional diagnostics or a more stringent follow-up regimen would be cost-effective.