Helena C. van Doorn

Endometrial thickness measurement for detecting endometrial cancer in women with postmenopausal bleeding: a systematic review and meta-analysis

OBJECTIVE: To estimate the accuracy of endometrial thickness measurement in the detection of endometrial cancer among women with postmenopausal bleeding with individual patient data using different meta-analytic strategies. DATA SOURCES: Original data sets of studies detected after reviewing the included studies of three previous reviews on this subject. An additional literature search of published articles using MEDLINE databases was preformed from January 2000 to December 2006 to identify articles reporting on endometrial carcinoma and sonographic endometrial thickness measurement in women with postmenopausal bleeding. METHODS OF STUDY SELECTION: We identified 90 studies reporting on endometrial thickness measurements and endometrial carcinoma in women with postmenopausal bleeding. TABULATION, INTEGRATION, AND RESULTS: We contacted 79 primary investigators to obtain the individual patient data of their reported studies, of which 13 could provide data. Data on 2,896 patients, of which 259 had carcinoma, were included. Several approaches were used in the analyses of the acquired data. First, we performed receiver operator characteristics (ROC) analysis per study, resulting in a summary area under the ROC curve (AUC) calculated as a weighted mean of AUCs from original studies. Second, individual patient data were pooled and analyzed with ROC analyses irrespective of study with standardization of distributional differences across studies using multiples of the median and by random effects logistic regression. Finally, we also used a two-stage procedure, calculating sensitivities and specificities for each study and using the bivariate random effects model to estimate summary estimates for diagnostic accuracy. This resulted in rather comparable ROC curves with AUCs varying between 0.82 and 0.84 and summary estimates for sensitivity and specificity located along these curves. These curves indicated a lower AUC than previously reported meta-analyses using conventional techniques. CONCLUSION: Previous meta-analyses on endometrial thickness measurement probably have overestimated its diagnostic accuracy in the detection of endometrial carcinoma. We advise the use of cutoff level of 3 mm for exclusion of endometrial carcinoma in women with postmenopausal bleeding.

Small bites versus large bites for closure of abdominal midline incisions (STITCH): A double-blind, multicentre, randomised controlled trial

BACKGROUND Incisional hernia is a frequent complication of midline laparotomy and is associated with high morbidity, decreased quality of life, and high costs. We aimed to compare the large bites suture technique with the small bites technique for fascial closure of midline laparotomy incisions. METHODS We did this prospective, multicentre, double-blind, randomised controlled trial at surgical and gynaecological departments in ten hospitals in the Netherlands. Patients aged 18 years or older who were scheduled to undergo elective abdominal surgery with midline laparotomy were randomly assigned (1:1), via a computer-generated randomisation sequence, to receive small tissue bites of 5 mm every 5 mm or large bites of 1 cm every 1 cm. Randomisation was stratified by centre and between surgeons and residents with a minimisation procedure to ensure balanced allocation. Patients and study investigators were masked to group allocation. The primary outcome was the occurrence of incisional hernia; we postulated a reduced incidence in the small bites group. We analysed patients by intention to treat. This trial is registered at Clinicaltrials.gov, number NCT01132209 and with the Nederlands Trial Register, number NTR2052. FINDINGS Between Oct 20, 2009, and March 12, 2012, we randomly assigned 560 patients to the large bites group (n=284) or the small bites group (n=276). Follow-up ended on Aug 30, 2013; 545 (97%) patients completed follow-up and were included in the primary outcome analysis. Patients in the small bites group had fascial closures sutured with more stitches than those in the large bites group (mean number of stitches 45 [SD 12] vs 25 [10]; p<0·0001), a higher ratio of suture length to wound length (5·0 [1·5] vs 4·3 [1·4]; p<0·0001) and a longer closure time (14 [6] vs 10 [4] min; p<0·0001). At 1 year follow-up, 57 (21%) of 277 patients in the large bites group and 35 (13%) of 268 patients in the small bites group had incisional hernia (p=0·0220, covariate adjusted odds ratio 0·52, 95% CI 0·31-0·87; p=0·0131). Rates of adverse events did not differ significantly between groups. INTERPRETATION Our findings show that the small bites suture technique is more effective than the traditional large bites technique for prevention of incisional hernia in midline incisions and is not associated with a higher rate of adverse events. The small bites technique should become the standard closure technique for midline incisions. FUNDING Erasmus University Medical Center and Ethicon.

Progesterone inhibition of Wnt/β-catenin signaling in normal endometrium and endometrial cancer

Purpose. Wnt signaling regulates the fine balance between stemness and differentiation. Here, the role of Wnt signaling to maintain the balance between estrogen-induced proliferation and progesterone-induced differentiation during the menstrual cycle, as well as during the induction of hyperplasia and carcinogenesis of the endometrium, was investigated. Experimental Design: Endometrial gene expression profiles from estradiol (E2) and E2 + medroxyprogesterone acetate–treated postmenopausal patients were combined with profiles obtained during the menstrual cycle (PubMed; GEO DataSets). Ishikawa cells were transfected with progesterone receptors and Wnt inhibitors dickkopf homologue 1 (DKK1) and forkhead box O1 (FOXO1), measuring Wnt activation. Expression of DKK1 and FOXO1 was inhibited by use of sequence-specific short hairpins. Furthermore, patient samples (hormone-treated endometria, hyperplasia, and endometrial cancer) were stained for Wnt activation using nuclear β-catenin and CD44. Results: In vivo, targets and components of the Wnt signaling pathway (among them DKK1 and FOXO1) are regulated by E2 and progesterone. In Wnt-activated Ishikawa cells, progesterone inhibits Wnt signaling by induction of DKK1 and FOXO1. Furthermore, using siRNA-mediated knockdown of both DKK1 and FOXO1, progesterone inhibition of Wnt signaling was partly circumvented. Subsequently, immunohistochemical analysis of the Wnt target gene CD44 showed that progesterone acted as an inhibitor of Wnt signaling in hyperplasia and in well-differentiated endometrial cancer. Conclusion: Progesterone induction of DKK1 and FOXO1 results in inhibition of Wnt signaling in the human endometrium. This Wnt inhibitory effect of progesterone is likely to play a rate-limiting role in the maintenance of endometrial homeostasis and, on its loss, in tumor onset and progression toward malignancy. (Clin Cancer Res 2009;15(18):5784–93)

Prospective evaluation of molecular screening for Lynch syndrome in patients with endometrial cancer ≤70 years

OBJECTIVE Lynch syndrome (LS) is a hereditary syndrome that predisposes to multiple malignancies including endometrial cancer (EC). We aimed to evaluate a diagnostic strategy for LS based on routine analysis of microsatellite instability (MSI) and immunohistochemical (IHC) staining for mismatch repair (MMR) proteins in tumour tissue of all newly diagnosed EC patients ≤ 70 years. METHODS Consecutive EC patients ≤ 70 years were included prospectively in eight Dutch centres. EC specimens were analysed for MSI, IHC of four MMR proteins, MMR gene methylation status and BRAF-mutations. tumours were classified as; 1) likely to be caused by LS, 2) sporadic MSI-H, or 3) microsatellite stable (MSS). RESULTS Tumour specimens of 179 patients (median age 61 years, IQR 57-66) were analysed. In our study 92% of included patients were over 50 years of age. Eleven EC patients were found likely to have LS (6%; 95% CI 3-11%), including 1 patient suspected of an MLH1, 2 of an MSH2, 6 of an MSH6 and 2 of a PMS2 gene defect. Germline mutation analyses revealed 7 MMR gene germline mutations. Ten patients likely to have LS (92%) were older than 50 years. In addition, 31 sporadic MSI-H tumours with MLH1 promoter hypermethylation (17%; 95% CI 13-24%) were identified. CONCLUSIONS Molecular screening for LS in patients with EC diagnosed ≤ 70 years, leads to identification of a profile likely to have LS in 6% of cases. New screening guidelines for LS are needed, including recommendations for EC patients older than 50 years of age.

A multicenter randomized controlled trial evaluating the effect of small stitches on the incidence of incisional hernia in midline incisions

BackgroundThe median laparotomy is frequently used by abdominal surgeons to gain rapid and wide access to the abdominal cavity with minimal damage to nerves, vascular structures and muscles of the abdominal wall. However, incisional hernia remains the most common complication after median laparotomy, with reported incidences varying between 2-20%. Recent clinical and experimental data showed a continuous suture technique with many small tissue bites in the aponeurosis only, is possibly more effective in the prevention of incisional hernia when compared to the common used large bite technique or mass closure.Methods/DesignThe STITCH trial is a double-blinded multicenter randomized controlled trial designed to compare a standardized large bite technique with a standardized small bites technique. The main objective is to compare both suture techniques for incidence of incisional hernia after one year. Secondary outcomes will include postoperative complications, direct costs, indirect costs and quality of life.A total of 576 patients will be randomized between a standardized small bites or large bites technique. At least 10 departments of general surgery and two departments of oncological gynaecology will participate in this trial. Both techniques have a standardized amount of stitches per cm wound length and suture length wound length ratios are calculated in each patient. Follow up will be at 1 month for wound infection and 1 year for incisional hernia. Ultrasound examinations will be performed at both time points to measure the distance between the rectus muscles (at 3 points) and to objectify presence or absence of incisional hernia. Patients, investigators and radiologists will be blinded during follow up, although the surgeon can not be blinded during the surgical procedure.ConclusionThe STITCH trial will provide level 1b evidence to support the preference for either a continuous suture technique with many small tissue bites in the aponeurosis only or for the commonly used large bites technique.Trial registrationClinicaltrials.gov NCT01132209

A novel SRY missense mutation affecting nuclear import in a 46,XY female patient with bilateral gonadoblastoma

Patients with disorders of sex development (DSD), especially those with gonadal dysgenesis and hypovirilization, are at risk of developing the so-called type II germ cell tumors (GCTs). Both carcinoma in situ and gonadoblastoma (GB) can be the precursor lesion, resulting in a seminomatous or non-seminomatous invasive cancer. SRY mutations residing in the HMG domain are found in 10–15% of 46,XY gonadal dysgenesis cases. This domain contains two nuclear localization signals (NLSs). In this study, we report a unique case of a phenotypical normal woman, diagnosed as a patient with 46,XY gonadal dysgenesis, with an NLS missense mutation, on the basis of the histological diagnosis of a unilateral GB. The normal role of SRY in gonadal development is the upregulation of SOX9 expression. The premalignant lesion of the initially removed gonad was positive for OCT3/4, TSPY and stem cell factor in germ cells, and for FOXL2 in the stromal component (ie, granulosa cells), but not for SOX9. On the basis of these findings, prophylactical gonadectomy of the other gonad was performed, also showing a GB lesion positive for both FOXL2 (ovary) and SOX9 (testis). The identified W70L mutation in the SRY gene resulted in a 50% reduction in the nuclear accumulation of the mutant protein compared with wild type. This likely explains the diminished SOX9 expression, and therefore the lack of proper Sertoli cell differentiation during development. This case shows the value of the proper diagnosis of human GCTs in identification of patients with DSD, which allows subsequent early diagnosis and prevention of the development of an invasive cancer, likely to be treated by chemotherapy at young age.

Management of recurrent endometrioid endometrial carcinoma: An overview

In this paper, an overview of the literature on the management of recurrent endometrial cancer is presented, focusing on patients with histopathologic endometrioid type of tumors. The different treatment modalities are described, and a management recommendation scheme is presented. Indications for surgical treatment depend on resectability, site and size of the tumor, and performance status of the patient. Indications for radiotherapy depend on the site of the recurrence and also on the initial therapy received. When considering systemic treatment for patients with recurrent endometrial cancer, it is important to take into account the general health status and condition of the patient as well as which prior therapy the patient has received. The treatments of choice for patients with hormone-sensitive tumors (positive receptor levels, low-grade tumors, and long disease-free interval) are progestagens as first-line treatment and tamoxifen as second-line treatment. Patients with high-grade tumors, negative hormone receptor levels, and short treatment-free interval are best treated with chemotherapy. Paclitaxel, doxorubicin, and cisplatin are the most active combination therapy for these patients but with significant toxicity. In phase II studies, the combination therapy with paclitaxel and carboplatin seems to be as effective but less toxic and can be administered in outpatient clinic. The literature on the management of patients with recurrent endometrial cancer is discussed in detail. The different sites of recurrent disease (ie, local, regional, and/or distant) are evaluated separately; management recommendations are proposed, and alternative approaches are given.

Incidence and Survival Trends of Uncommon Corpus Uteri Malignancies in the Netherlands, 1989–2008

Introduction Corpus uteri cancer is the most common malignancy of the female reproductive tract in industrialized countries, and its incidence is increasing. Although most of these tumors are of the common endometrial type, there are also many uncommon tumors of the corpus uteri. We examined the incidence and survival of patients with uncommon epithelial tumors, carcinosarcomas, and sarcomas of the corpus uteri diagnosed since 1989. Methods All common and uncommon malignancies of the corpus uteri registered in the nationwide population-based Netherlands Cancer Registry (NCR) during 1989–2008 were included (n = 30,960). The histological subtypes were described according to the Blaustein classification system. Age-standardized incidence for 1989–2008 was calculated per 1,000,000 person-years (p-y), and relative survival was calculated according to the type of uncommon tumor. Results The incidence of corpus uteri malignancies increased from 159 to 177 per 1,000,000 p-y, mainly owing to the rise in endometrioid adenocarcinomas from 106 to 144 per 1,000,000 p-y. In contrast, the incidence of uncommon epithelial endometrial carcinomas (UEECs) decreased from 30 to 13 per 1,000,000 p-y, although carcinosarcomas increased slightly from 5.1 to 6.9 per 1,000,000 p-y. Furthermore, a remarkable shift in incidence of endometrial stromal cell sarcomas (ESS) was observed from high-grade ESSs to low-grade ESSs after 2003. Five-year relative survival for patients with UEEC decreased from 72% to 54% and for patients with serous adenocarcinoma from 73% to 51%. Coinciding with an increase in the incidence of common adenocarcinoma of the corpus uteri, there was a decline in uncommon adenocarcinomas and more or less a stable incidence of sarcomas and carcinosarcomas. Conclusion The decrease in UEEC tumors consisted largely of fewer serous carcinomas, possibly and likely reflecting a more precise histopathological classification of villoglandular tumors. Unfortunately, relative survival for patients with UEEC, sarcomas, and carcinosarcomas did not improve over the study period, indicating a need for more research on treatment strategies for this group of patients.

Lymph node count at inguinofemoral lymphadenectomy and groin recurrences in vulvar cancer

Objective The objective of the study is to determine the risk factors for groin recurrence (GR) in patients with primary vulvar squamous cell carcinoma (SCC) after inguinofemoral lymphadenectomy (IFL) without lymph node metastases and/or adjuvant chemoradiotherapy. Methods The study is a multicenter retrospective review of clinical and histopathological data of patients with lymph node–negative vulvar SCC who underwent an IFL. Patients with and without GRs were compared to identify risk factors. Results In 134 patients, 252 groins were eligible for the analyses—16 patients underwent ipsilateral IFL and 118 patients underwent bilateral IFL. Groin recurrences occurred in 4 (1.6%) of the 252 dissected groins. Besides, 1 patient who underwent ipsilateral IFL had a recurrence in the nonoperated contralateral groin; this groin was left out of analysis. The median number of dissected nodes per groin was 9.8 (range, 1–38) in all patients and 6.5 (range, 5–8) in patients with GR. Multivariate analyses showed that GR was related to poor differentiation (P = 0.04), and node count less than 9 (P = 0.04), no association with age, tumor localization, tumor diameter, focality, invasion depth, or stage was found. Nineteen patients with both low node count and poor differentiation had 19% GRs. Survival analyses showed less favorable survival in patients with poor differentiation. Conclusions The overall risk of developing GR after negative IFL in patients with vulvar SCC is low (1.6% per groin) but significantly higher in patients with tumors with a poor differentiation and lymph node count less than 9 at IFL. A large well-designed prospective study is needed to evaluate closer surveillance in patients at risk.

Results of concurrent chemotherapy and hyperthermia in patients with recurrent cervical cancer after previous chemoradiation

Abstract Background: Concomitant hyperthermia has been shown to improve response rate after cisplatin in recurrent cervical cancer in previously irradiated patients. It is unclear whether similar response rates can be obtained in patients with a recurrence after previous platinum-containing chemoradiation. Objective: This study aimed to evaluate the outcome of cisplatin-based chemotherapy with concurrent hyperthermia in patients with recurrent cervical cancer after radiotherapy and cisplatin. Methods: Patients with recurrent cervical cancer after cisplatin-based chemoradiation or neoadjuvant chemotherapy followed by surgery and radiotherapy who were treated with concurrent platinum-based chemotherapy and hyperthermia were eligible for this retrospective analysis. All patients received six or eight weekly platinum-based chemotherapy cycles in combination with six or eight weekly hyperthermia sessions. The time-to-event variables were estimated using Kaplan-Meier analysis. P-values less than 0.05 were considered significant. Results: All 38 evaluable patients were selected from the hyperthermia database in the Academic Medical Centre (Amsterdam) and the Erasmus Medical Centre (Rotterdam). Mean age at relapse was 45.7 years (range 27–74). Median time to recurrence after first-line treatment was 15 months. A total of 27 patients had a local and/or regional recurrence; 11 had disease beyond the pelvis. All planned courses of cisplatin chemotherapy and hyperthermia were administered in 17/38 patients. Median follow-up was 6.5 months. One patient died during treatment; response rate was 4/37 (14%), with one complete response. Overall survival was 23% at 12 months and 4% at 24 months. The incidence of grade 3–4 haematological complications did not exceed 10%. Conclusion: In this retrospective study, concurrent cisplatin and hyperthermia after first-line cisplatin-containing chemoradiation showed poor response and survival. We do not recommend this treatment for recurrence of locally advanced cervical cancer.