Lymph node detection by MRI before and after a systematic pelvic lymphadenectomy.

OBJECTIVE: Pelvic lymphadenectomy is considered the gold standard to diagnose and possibly treat lymphatic metastases in gynaecological cancer patients. The aim of this study is to evaluate whether all presurgical MRI detected lymph nodes were removed during the systematic pelvic lymph node dissection (PLND) in cervical cancer patients. METHODS: 21 consecutive cervical cancer patients who were scheduled to undergo a PLND were evaluated by a MRI scan prior to surgery and 6 weeks afterwards. All patients had tumour metastasis negative lymph nodes at histopathological examination. RESULTS: On average, 10 pelvic lymph nodes (range 5-17) per patient were detected by presurgical MRI. Postsurgical MRI scans showed that on average 1 (range 0-3) pelvic node per patient was not removed by surgery. In total, 14% of the presurgical MR detected nodes were not removed by surgery (31/225). Approximately half of all lymph nodes that remained after surgery were located in the obturator region. In spite of the remaining nodes, surgery and histopathological examination did detect more nodes than MRI: on average 21 lymph nodes per patient (range 9-59) were removed. Another 2 lymph nodes (range 0-6 per patient) were judged to be newly developed after surgery. CONCLUSION: Although surgery was able to remove many more lymph nodes than those detected by presurgical MRI, 14% of presurgical MRI detected lymph nodes were not removed by PLND. The value of MRI prior to surgery for the detection of pathological lymph nodes is a subject of further research.

Hypoxia-inducible factor 1 alpha is essential for hypoxic p27 induction in endometrioid endometrial carcinoma.

Hypoxia-inducible factor 1alpha (HIF-1alpha) plays an essential role in the adaptive response of cells to hypoxia. The cyclin-dependent kinase inhibitor p27(Kip1) is highly expressed in the normal endometrium but is lost during endometrial carcinogenesis. However, in high-grade cancers, p27 re-expression is observed. We analysed the role of HIF-1alpha in hypoxia-induced expression of p27 in vitro and in vivo in endometrial cancer. Paraffin-embedded specimens from endometrioid endometrial carcinoma (n = 39) were stained immunohistochemically for HIF-1alpha, p27, and Ki67. HEC1B, an endometrial carcinoma cell line, was cultured under normoxic or hypoxic conditions in the presence or absence of transiently expressed short hairpin RNAs targeting HIF-1alpha. Protein expression of p27 and HIF-1alpha was assessed by western blotting. Immunohistochemical staining revealed perinecrotic HIF-1alpha expression in 67% of the cases and p27 staining centrally in the tumour islands, mostly around necrosis, in 46% of the cases. In 50% of the tumours with perinecrotic HIF-1alpha expression, p27 and HIF-1alpha perinecrotic/central co-localization was observed. In these tumour sections, hypoxia-associated p27 expression showed less proliferation around necrosis. Analysis of cultured endometrial carcinoma cells demonstrated that p27 protein expression is induced by hypoxia. This induction was abrogated by transient knockdown of HIF-1alpha using RNAi. Furthermore, hypoxia induced cell cycle arrest in HEC1B cells. We conclude that, in endometrioid endometrial carcinoma, p27 re-expression by hypoxia is HIF-1alpha-dependent and leads to cell cycle arrest. This may contribute to the survival of cancer cells in hypoxic parts of the tumour.

Progressive derailment of cell cycle regulators in endometrial carcinogenesis.

BACKGROUND: Derailments of the control mechanisms of the cell cycle can initiate carcinogenesis, and play a role in progression to cancer. AIM: To explore the expression of cell cycle proteins in normal, premalignant and malignant endometrial lesions representing the morphologically well defined stepwise model of human endometrial carcinogenesis METHODS: Observational study. Paraffin-embedded specimens from inactive endometrium (n = 16), endometrial hyperplasia (n = 23) and endometrioid endometrial carcinoma (n = 39) were stained immunohistochemically for cyclin A, cyclin B1, cyclin D1, cyclin E, cdk2, p16, p21, p27, p53 and Ki67(MIB-1)). Differences in expression between the tissues, and correlation with classical prognostic factors for the carcinomas were analysed. RESULTS: Expression of cyclin A and Ki67 gradually increased from normal through hyperplasia to carcinoma, indicating that proliferation increases over the carcinogenetic spectrum. cdk2, p16 and p21 gradually increased from normal through hyperplasia to carcinoma, indicating their potential importance in both early and late carcinogenesis. Cyclin D1, cyclin E and p53 especially increased and p27 decreased from hyperplasia to carcinoma, underlining their role in late carcinogenesis. In cancers, expression of cyclin A, p53 and Ki67 was positively correlated to grade, and cyclin A was positively correlated with cdk2, p21, Ki67, cyclin E and p53. CONCLUSION: During (endometrioid) endometrial carcinogenesis, there is increasing proliferation paralleled by progressive derailment of cyclin B1, cyclin D1, cyclin E, p16, p21, p27, p53, and cdk2, indicating the importance of these cell cycle regulators in endometrial carcinogenesis.

Symptomatic candidiasis: Using self sampled vaginal smears to establish the presence of Candida, lactobacilli, and Gardnerella vaginalis.

In a prospective cohort study, 10 symptomatic women with recurrent vulvovaginal candidiasis were taught how to prepare vaginal smears of their own vaginal fluids on days 7, 14, 21, and 28. The 40 smears were stained with the PAS-method and examined by three different cytopathologists for presence of Candida. Thereafter, the smears were restained with Giemsa-stain to determine presence of lactobacilli, Gardnerella vaginalis ("clue cells") and neutrophils. All three cytopathologists unequivocally established Candida blastospores and (pseudo)hyphae in 27 out of the 40 PAS-stained vaginal smears, whereas in the remaining 13 smears Candida was not found. All 10 patients had Candida in their smears during the second half of their menstrual cycle.Self sampled smears prove to be reliable for establishing the presence of Candida in symptomatic patients with candidiasis. Candida is associated with a lactobacillus-predominated vaginal flora, but with the absence of Gardnerella vaginalis. Further studies may be directed towards the interaction between the various members of the vaginal flora. This study should open molecular methodology for determining the possible interactions of lactobacilli and Candida.

[Settlement effected for damages for victims of diethylstilbestrol (DES)]. / Regeling voor schadevergoeding aan slachtoffers van di-ethylstilbestrol (des) een feit.

In 2007 the Dutch DESFonds (DES Fund) starts payment to victims of exposure to diethylstilbestrol in a collective settlement. This is unique in the world because the arrangement covers the entire range of DES-related disorders and individual persons do not have to start an expensive and emotionally taxing legal procedure with uncertain outcome, which would last several years. Individuals can now be compensated based on medical evidence of DES exposure and the presence of a DES-related disorder covered by the settlement. In close collaboration with the DES Centre (an association of DES victims) a careful procedure was followed before this settlement was realised. The Dutch Expert Committee on DES-related Health Effects first reviewed the literature for evidence and established a list of disorders with a causal association with DES. For each DES-related disorder covered by the settlement, the appropriate compensation was determined by the attributive risk and the severity of the disease. The settlement is the result of close collaboration between all parties involved.

p16 is consistently expressed in endometrial tubal metaplasia.

BACKGROUND: Cell cycle proteins and HIF-1alpha with downstream factors are often abberrantly expressed in (pre)neoplastic tissue. METHODS: Paraffin-embedded specimens of inactive endometrium with TM (n=15), ovarian inclusion cysts (n=6), cervix with TM (tubal metaplasia) (n=3), Fallopian tubes (n=7), cycling endometrium (n=9) and a ciliated cell tumor of the ovary were stained for p16 and LhS28. 39 Endometrioid endometrial carcinomas and 5 serous endometrial carcinomas were stained for p16. Additionally, inactive endometrium (n=15) was immunohistochemically stained for p21, p27, p53, cyclin A, cyclin D1, cyclin E, HIF-1alpha, CAIX, Glut-1 and MIB-1. RESULTS: A mosaic pattern of expression of p16 was seen throughout in all cases of endometrial TM (15/15), in 2/6 of the ovarian inclusion cysts with TM, in all (3/3) cervical TM and focal in 5/7 of Fallopian tube cases. Mosaic expression was also seen in a ciliated cell tumor of the ovary and in 18/39 of endometrioid endometrial carcinomas, and diffuse p16 expression was seen in 5/5 serous carcinomas. In comparison with normal endometrium, TM areas in the endometrium showed significantly increased expression of HIF-1alpha, cyclin E, p21 and cyclin A, and decreased expression of p27. Membranous expression of CAIX and Glut-1 was only seen in TM areas, pointing to functional HIF-1alpha. CONCLUSION: As p16 is consistently expressed in TM, less and only patchy expressed in the normal Fallopian tube, is paralleled by aberrant expression of cell cycle proteins, HIF-1alpha, CAIX and Glut-1 and resembles the pattern of p16 expression frequently seen in endometrial carcinomas, we propose endometrial TM to be a potential premalignant endometrial lesion.

Is there an association between depressive and urinary symptoms during and after pregnancy?

Depressive symptoms and urinary symptoms are both highly prevalent in pregnancy. In the general population, an association is reported between urinary symptoms and depressive symptoms. The association of depressive and urinary symptoms has not yet been assessed in pregnancy. In this study, we assessed (1) the prevalence of depressive symptoms, over-active bladder (OAB) syndrome, urge urinary incontinence (UUI) and stress urinary incontinence (SUI) during and after pregnancy using the Center for Epidemiologic Studies Depression Scale (CES-D) and the Urogenital Distress Inventory (UDI) and (2) the association of depressive symptoms with urinary incontinence and over-active bladder syndrome during and after pregnancy, controlling for confounding socioeconomic, psychosocial, behavioural and biomedical factors in a cohort of healthy nulliparous women. Our data show a significant increase in prevalence of depressive symptoms, UUI, SUI and OAB during pregnancy and a significant reduction in prevalence of depressive symptoms, SUI and OAB after childbirth. UUI prevalence did not significantly decrease after childbirth. In univariate analysis, urinary incontinence and the OAB syndrome were significantly associated with a CES-D score indicative of a possible clinical depression at 36 weeks gestation. However, after adjusting for possible confounding factors, only the OAB syndrome remained significantly associated (OR 4.4 [1.8-10.5]). No association was found between depressive and urinary symptoms at 1 year post-partum. Only OAB was independently associated with depressive symptoms during pregnancy. Possible explanations for this association are discussed.

Lymph node recurrence following stage IA vulvar carcinoma: two cases and a short overview of literature.

Stage IA vulvar carcinoma is not supposed to metastasize to the lymph nodes. Therefore, it is assumed that these lesions can be safely treated by less aggressive methods than macroinvasive carcinomas. However, in this case report, two patients are described who had vulvar lesions with a depth of invasion of less than 1 mm and developed lymph node metastases in the groin despite radical wide local excision of their lesions. Both the patients underwent lymphadenectomy and received postoperative radiation therapy on the groins. Neither of the two patients died of vulvar carcinoma. Thus, we conclude that vigilance for the occurrence of lymph node metastases remains necessary after radical, local excision in stage IA vulvar cancer. However, this case report also shows that adequate treatment of groin node metastases can result in a very good long-term survival.

Improving the existing diagnostic strategy by accounting for characteristics of the women in the diagnostic work up for postmenopausal bleeding.

OBJECTIVES: The aim of this study was to evaluate whether the efficiency of the current diagnostic work up following postmenopausal bleeding could be improved by diagnostic strategies that take into account characteristics of the women in addition to the currently recommended transvaginal measurement of endometrial thickness to determine for subsequent histological assessment. DESIGN: Multicenter, prospective cohort study. SETTING: A university hospital and seven teaching hospitals in the Netherlands. SAMPLE: Consecutive women not using hormone replacement therapy, presenting with postmenopausal bleeding. METHODS: Five hundred and forty women underwent transvaginal sonography, and in case of endometrial thickness (double layer) above 4 mm, subsequent endometrial sampling was performed. Presence of carcinoma was ruled out by the absence of abnormalities in histological specimen or by an uneventful follow up of at least 6 months. MAIN OUTCOME MEASURES: Probability of endometrial carcinoma was estimated by multivariable logistic regression models. For each diagnostic strategy, we calculated diagnostic accuracy (area under receiver operating characteristic curve [AUC]), negative predictive value (NPV) and the number of diagnostic procedures. RESULTS: A strategy with transvaginal sonography alone with a fixed threshold incorrectly classified 0.7% of the women as nonmalignant (NPV: 99.3% [98.5-100%]), with 97% sensitivity and 56% specificity. A strategy integrating characteristics of the women with transvaginal sonography could result in less false reassurances (NPV: 99.6% [99.2-100%]), with only marginal decrease in diagnostic procedures, or a minor increase in false reassurances (NPV: 99.0% [98.3-100%]), with a substantial reduction (15-20%) in the procedures. AUCs associated with these strategies could improve from 0.76 (0.73-0.79) for transvaginal sonography alone to 0.90 (0.87-0.93) for the integrated strategy. CONCLUSION: Taking into account the characteristics of the women could increase the efficiency of the diagnostic work up for postmenopausal bleeding.

Feasibility and patient satisfaction with pelvic organ prolapse and urinary incontinence day surgery.

We performed a prospective cohort study to characterize the feasibility of urinary stress incontinence and pelvic organ prolapse surgery in day care. Two hundred and one women were prepared for day surgery by a standardised protocol; 132 women underwent a single Tension-free Vaginal Tape/Tension-free Vaginal Tape-Obturator procedure, and 69 women had additional or only pelvic organ prolapse surgery. The main outcome measures were complications, satisfaction score and recommendation to others, recorded after 3 days and 6-10 weeks. We found that it is feasible and safe to perform pelvic organ prolapse and urinary incontinence surgery in day care. Patients' satisfaction is high in all aspects of care and the majority would recommend it to others. In multivariate logistic regression analysis, only dissatisfaction with the care provided by the staff of the surgical ward was significantly associated with a negative recommendation to others (odds ratio 7.3, 95% confidence interval 1.6-33.5).

Which factors determine the sexual function 1 year after childbirth?

OBJECTIVE: To evaluate which factors determine sexual activity and satisfaction with the sexual relationship 1 year after the first delivery. DESIGN: Prospective longitudinal cohort study. SETTING: Ten midwifery practices. POPULATION: Three hundred and seventy-seven nulliparous women were included. METHODS: The Maudsley Marital Questionnaire is a standardised and validated questionnaire with 15 items relating to marital and sexual adjustment, with a nine-point (0-8) scale appended to each question. Scores on the sexual scale (MMQ-S) range from 0 to 40. Higher scores are indicative of greater dissatisfaction. Sexual intercourse was dichotomised into having sexual intercourse or not having sexual intercourse. Several obstetric and maternal factors were analysed. MAIN OUTCOME MEASUREMENTS: Sexual intercourse at 1 year postpartum and dissatisfaction with the sexual relationship as assessed by the MMQ-S scale. RESULTS: In multiple logistic regression analysis, the main predictive factor for no sexual intercourse 1 year postpartum was no sexual intercourse at 12 weeks of gestation (beta 11.0 [4.01-30.4]). Women were five times less likely to be sexually active after a third/fourth degree anal sphincter tear as compared with women with an intact perineum (beta 0.2 [0.04-0.93]). Dissatisfaction with the sexual relationship 1 year after childbirth, assessed with the MMQ-S scale, is associated with not being sexually active at 12 weeks of gestation (beta- 0.208, P= 0.004) and with an older maternal age at delivery (beta 0.405, P= 0.032). CONCLUSION: An important prognostic factor for dissatisfaction with the sexual relationship 1 year postpartum was not being sexually active in early pregnancy. Satisfaction with the sexual relationship seems not to depend on pregnancy- and parturition-associated factors.