64 results on '"Baal, WM"'
Search Results
2. P57 Value of circulating tumor DNA in the differentiation between malignant and benign ovarian tumors
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Lof, P, primary, Sistermans, EA, additional, Wessels, L, additional, Amant, F, additional, van den Broek, D, additional, Mom, CH, additional, Hemelaar, M, additional, van Baal, WM, additional, Verbruggen, M, additional, Rosier - van Dunné, F, additional, Hermsen, B, additional, Horlings, HM, additional, and Lok, CAR, additional
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- 2019
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3. Comparing the performance of FAM19A4 methylation analysis, cytology and HPV16/18 genotyping for the detection of cervical (pre)cancer in high-risk HPV-positive women of a gynecologic outpatient population (COMETH study)
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Luttmer, R, De Strooper, LMA, Berkhof, J, Snijders, PJF, Dijkstra, MG, Uijterwaal, MH, Steenbergen, RDM, van Kemenade, Folkert, Rozendaal, L, Helmerhorst, Verheijen, RHM, ter Harmsel, WA, van Baal, WM, Graziosi, PGCM, Quint, WGV, Heideman, DAM, Meijer, CJLM, Pathology, and Obstetrics & Gynecology
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SDG 3 - Good Health and Well-being ,female genital diseases and pregnancy complications - Abstract
Recently, DNA methylation analysis of FAM19A4 in cervical scrapes has been shown to adequately detect high-grade cervical intraepithelial neoplasia and cervical cancer (>= CIN3) in high-risk HPV (hrHPV)-positive women. Here, we compared the clinical performance of FAM19A4 methylation analysis to cytology and HPV16/18 genotyping, separately and in combination, for >= CIN3 detection in hrHPV-positive women participating in a prospective observational multi-center cohort study. The study population comprised hrHPV-positive women aged 18-66 years, visiting a gynecological outpatient clinic. From these women, cervical scrapes and colposcopy-directed biopsies (for histological confirmation) were obtained. Cervical scrapes were analyzed for FAM19A4 gene promoter methylation, cytology and HPV16/18 genotyping. Methylation analysis was performed by quantitative methylation-specific PCR (qMSP). Sensitivities and specificities for >= CIN3 were compared between tests. Stratified analyses were performed for variables that potentially influence marker performance. Of all 508 hrHPV-positive women, the sensitivities for >= CIN3 of cytology, FAM19A4 methylation analysis, and cytology combined with HPV16/18 genotyping were 85.6, 75.6 and 92.2%, respectively, with corresponding specificities of 49.8, 71.1 and 29.4%, respectively. Both sensitivity and specificity of FAM19A4 methylation analysis were associated with age (p = 30 years (n=287), >= CIN3 sensitivity of FAM19A4 methylation analysis was 88.3% (95% CI: 80.2-96.5) which was noninferior to that of cytology [85.5% (95% CI: 76.0-94.0)], at a significantly higher specificity [62.1% (95% CI: 55.8-68.4) compared to 47.6% (95% CI: 41.1-54.1)]. In conclusion, among hrHPV-positive women from an outpatient population aged >= 30 years, methylation analysis of FAM19A4 is an attractive marker for the identification of women with >= CIN3.
- Published
- 2016
4. Word catheter and marsupialisation in women with a cyst or abscess of the Bartholin gland (WoMan-trial): a randomised clinical trial
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Kroese, JA, primary, van der Velde, M, additional, Morssink, LP, additional, Zafarmand, MH, additional, Geomini, P, additional, van Kesteren, PJM, additional, Radder, CM, additional, van der Voet, LF, additional, Roovers, JPWR, additional, Graziosi, GCM, additional, van Baal, WM, additional, van Bavel, J, additional, Catshoek, R, additional, Klinkert, ER, additional, Huirne, JAF, additional, Clark, TJ, additional, Mol, BWJ, additional, and Reesink-Peters, N, additional
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- 2016
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5. A personalised eHealth programme reduces the duration until return to work after gynaecological surgery: results of a multicentre randomised trial
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Vonk Noordegraaf, A, primary, Anema, JR, additional, van Mechelen, W, additional, Knol, DL, additional, van Baal, WM, additional, van Kesteren, PJM, additional, Brölmann, HAM, additional, and Huirne, JAF, additional
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- 2014
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6. A personalised e Health programme reduces the duration until return to work after gynaecological surgery: results of a multicentre randomised trial.
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Vonk Noordegraaf, A, Anema, JR, Mechelen, W, Knol, DL, Baal, WM, Kesteren, PJM, Brölmann, HAM, and Huirne, JAF
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HOLISTIC medicine ,PHYSIOLOGY ,MEDICAL care ,HEALTH programs ,THERAPEUTICS - Abstract
Objective To evaluate the effectiveness of an eHealth intervention on recovery and return to work, after gynaecological surgery. Design Randomised multicentre trial that ran from March 2010 until September 2011. Setting Secondary care in seven general and university hospitals in the Netherlands. Population A cohort of 215 women (aged 18-65 years) who had a hysterectomy and/or laparoscopic adnexal surgery for a benign indication. Methods The women were randomly assigned to the intervention group ( n = 110) or the control group ( n = 105). The intervention group received an eHealth programme that provided personalised tailor-made pre- and postoperative instructions on the resumption of daily activities, including work, and tools to improve self-empowerment and to identify recovery problems. The control group was provided with access to a control website. Main outcome measures The primary outcome was the duration of sick leave until a full sustainable return to work. Secondary outcome measures were quality of life, general recovery, and pain intensity. Results In intention-to-treat analysis the eHealth intervention was effective on time to return to work (hazard ratio 1.43; 95% confidence interval 1.003-2.040; P = 0.048). The median duration of sick leave until a full sustainable return to work was 39 days (interquartile range 20-67 days) in the intervention group and 48 days (interquartile range 21-69 days) in the control group. After 26 weeks pain intensity was lower (visual analogue scale, cumulative odds ratio 1.84; 95% confidence interval 1.04-3.25; P = 0.035) and quality of life was higher (Rand-36 health survey, between-group difference 30, 95% confidence interval 4-57; P = 0.024) in the intervention group, compared with the control group. Conclusions The use of the eHealth intervention by women after gynaecological surgery results in a faster return to work, with a higher quality of life and less pain. [ABSTRACT FROM AUTHOR]
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- 2014
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7. F211 Effects of 3 months low-dose HRT on parameters of cardiac function in postmenopausal women
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Mijatovic, V., primary, van Baal, WM, additional, Kamp, O, additional, van der Mooren, MJ, additional, Temmink-van der Hulst, CM, additional, Voetberg, GA, additional, Visser, CA, additional, and Kenemans, P., additional
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- 1996
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8. Effects of transdermal and oral postmenopausal hormone therapy on vascular function: a randomized, placebo-controlled study in healthy postmenopausal women.
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Hemelaar M, van der Mooren MJ, van Baal WM, Schalkwijk CG, Kenemans P, Stehouwer CDA, Hemelaar, Majoie, van der Mooren, Marius J, van Baal, W Marchien, Schalkwijk, Casper G, Kenemans, Peter, and Stehouwer, Coen D A
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- 2005
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9. Effects of low-dose oral and transdermal estrogen replacement therapy on hemostatic factors in healthy postmenopausal women: a randomized placebo-controlled study.
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Post MS, van der Mooren MJ, van Baal WM, Blankenstein MA, Merkus HMW, Kroeks MVA, Franke HR, Kenemans P, Stehouwer CDA, Post, Marinka S, van der Mooren, Marius J, van Baal, W Marchien, Blankenstein, Marinus A, Merkus, Hans M W M, Kroeks, Maurice V A M, Franke, Henk R, Kenemans, Peter, and Stehouwer, Coen D A
- Abstract
Objective: This study was undertaken to investigate the effect of transdermal and oral estrogen replacement therapy in healthy postmenopausal women on markers of coagulation and fibrinolysis associated with coronary artery disease.Study Design: In a randomized, placebo-controlled, double-blind study, healthy hysterectomized postmenopausal women received daily either placebo (n=49), transdermal 17beta-estradiol (E(2)) 50 microg (tE(2) group, n=33), oral E(2) 1 mg (oE(2) group, n=37), or oral E(2) 1 mg combined with gestodene 25 microg (oE(2)+G group, n=33) for thirteen 28-day treatment cycles. Hemostatic variables were measured in blood samples collected at baseline and in cycles 4 and 13.Results: No significant changes versus baseline and placebo were found in the tE(2) group, except for plasminogen activator inhibitor type-1 (PAI-1) in cycle 13 (-32.4%, P=.01). In the oE(2) group, significant percentage changes from baseline versus placebo in cycle 13 were found in fibrinogen, -5.4% (P<.05); factor VII, -7.3% (P<.05); thrombin-antithrombin III complexes, -13.3% (P<.05); tissue-type plasminogen activator (t-PA), -17.3% (P<.001); and PAI-1, -54.3% (P<.001). In the oE(2)+G group, respective changes were factor VII, -17.6% (P<.001); t-PA, -14.5% (P=.01); PAI-1, -36.4% (P<.01); and D-dimer, +21.8% (P<.05). No significant changes were observed in prothrombin fragment 1+2 and plasmin-alpha(2)-antiplasmin complexes.Conclusion: Low-dose oral estradiol therapy was associated with an increase in fibrinolysis and small decreases in procoagulant variables. Transdermal therapy had minor effects. [ABSTRACT FROM AUTHOR]- Published
- 2003
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10. Single-layer vs double-layer uterine closure during cesarean delivery: 3-year follow-up of a randomized controlled trial (2Close study).
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Verberkt C, Stegwee SI, Van der Voet LF, Van Baal WM, Kapiteijn K, Geomini PMAJ, Van Eekelen R, de Groot CJM, de Leeuw RA, and Huirne JAF
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- Humans, Female, Pregnancy, Adult, Double-Blind Method, Follow-Up Studies, Suture Techniques, Uterus surgery, Cicatrix etiology, Cicatrix prevention & control, Pregnancy Rate, Live Birth, Netherlands, Uterine Rupture etiology, Cesarean Section methods
- Abstract
Background: The rising rate of cesarean deliveries has led to an increased incidence of long long-term complications, including niche formation in the uterine scar. Niche development is associated with various gynecologic complaints and complications in subsequent pregnancies, such as uterine rupture and placenta accreta spectrum disorders. Although uterine closure technique is considered a potential risk factor for niche development, consensus on the optimal technique remains elusive., Objective: We aimed to evaluate the effect of single-layer vs double-layer closure of the uterine incision on live birth rate at a 3-year follow-up with secondary objectives focusing on gynecologic, fertility, and obstetrical outcomes at the same follow-up., Study Design: A multicenter, double-blind, randomized controlled trial was performed at 32 hospitals in the Netherlands. Women ≥18 years old undergoing a first cesarean delivery were randomly assigned (1:1) to receive either single-layer or double-layer closure of the uterine incision. The primary outcome of the long-term follow-up was the live birth rate; with secondary outcomes, including pregnancy rate, the need for fertility treatment, mode of delivery, and obstetrical and gynecologic complications. This trial is registered on the International Clinical Trials Registry Platform www.who.int (NTR5480; trial finished)., Results: Between 2016 and 2018, the 2Close study randomly assigned 2292 women, with 830 of 1144 and 818 of 1148 responding to the 3-year questionnaire in the single-layer and double-layer closure. No differences were observed in live birth rates; also there were no differences in pregnancy rate, need for fertility treatments, mode of delivery, or uterine ruptures in subsequent pregnancies. High rates of gynecologic symptoms, including spotting (30%-32%), dysmenorrhea (47%-49%), and sexual dysfunction (Female Sexual Function Index score, 23) are reported in both groups., Conclusion: The study did not demonstrate the superiority of double-layer closure over single-layer closure in terms of reproductive outcomes after a first cesarean delivery. This challenges the current recommendation favoring double-layer closure, and we propose that surgeons can choose their preferred technique. Furthermore, the high risk of gynecologic symptoms after a cesarean delivery should be discussed with patients., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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11. The effect of prior hysterosalpingo-foam sonography or hysterosalpingography on tubal patency: a secondary analysis of a randomized controlled trial.
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Kamphuis D, van Welie N, van Rijswijk J, van Hooff MHA, de Bruin JP, Verhoeve HR, Mol F, van Baal WM, Lambalk CB, Stoker J, van Wely M, Bossuyt PMM, Mol BWJ, Dreyer K, and Mijatovic V
- Abstract
Study Question: Does hysterosalpingo-foam sonography (HyFoSy) prior to hysterosalpingography (HSG) or HSG prior to HyFoSy affect visible tubal patency when compared HSG or HyFoSy alone?, Summary Answer: Undergoing either HyFoSy or HSG prior to tubal patency testing by the alternative method does not demonstrate a significant difference in visible tubal patency when compared to HyFoSy or HSG alone., What Is Known Already: HyFoSy and HSG are two commonly used visual tubal patency tests with a high and comparable diagnostic accuracy for evaluating tubal patency. These tests may also improve fertility, although the underlying mechanism is still not fully understood. One of the hypotheses points to a dislodgment of mucus plugs that may have disrupted the patency of the Fallopian tubes., Study Design, Size, Duration: This is a secondary analysis of the randomized controlled FOAM study, in which women underwent tubal patency testing by HyFoSy and HSG, randomized for order of the procedure. Participants either had HyFoSy first and then HSG, or vice versa. Here, we evaluate the relative effectiveness of tubal patency testing by HyFoSy or HSG prior to the alternative tubal patency testing method on visible tubal patency, compared to each method alone., Participants/materials, Setting, Methods: Infertile women aged between 18 and 41 years scheduled for tubal patency testing were eligible for participating in the FOAM study. Women with anovulatory cycles, endometriosis, or with a partner with male infertility were excluded. To evaluate the effect HyFoSy on tubal patency, we relied on HSG results by comparing the proportion of women with bilateral tubal patency visible on HSG in those who underwent and who did not undergo HyFoSy prior to their HSG (HyFoSy prior to HSG versus HSG alone). To evaluate the effect of HSG on tubal patency, we relied on HyFoSy results by comparing the proportion of women with bilateral tubal patency visible on HyFoSy in those who underwent and who did not undergo HSG prior to their HyFoSy (HSG prior to HyFoSy versus HyFoSy alone)., Main Results and the Role of Chance: Between May 2015 and January 2019, we randomized 1160 women (576 underwent HyFoSy first followed by HSG, and 584 underwent HSG first followed by HyFoSy). Among the women randomized to HyFoSy prior to HSG, bilateral tubal patency was visible on HSG in 467/537 (87%) women, compared with 472/544 (87%) women who underwent HSG alone (risk difference 0.2%; 95% CI: -3.8% to 4.2%). Among the women randomized to HSG prior to HyFoSy, bilateral tubal patency was visible on HyFoSy in 394/471 (84%) women, compared with 428/486 (88%) women who underwent HyFoSy alone (risk difference -4.4%; 95% CI: -8.8% to 0.0%)., Limitations, Reasons for Caution: The results of this secondary analysis should be interpreted as exploratory and cannot be regarded as definitive evidence. Furthermore, it has to be noted that pregnancy outcomes were not considered in this analysis., Wider Implications of the Findings: Tubal patency testing by either HyFoSy or HSG, prior to the alternative tubal patency testing method does not significantly affect visible tubal patency, when compared to alternative method alone. This suggests that both methods may have comparable abilities to dislodge mucus plugs in the Fallopian tubes., Study Funding/competing Interest(s): The FOAM study was an investigator-initiated study, funded by ZonMw, a Dutch organization for Health Research and Development (project number 837001504). IQ Medical Ventures provided the ExEm®-FOAM kits free of charge. The funders had no role in study design, collection, analysis, or interpretation of the data. H.R.V. reports consultancy fees from Ferring. M.v.W. received a travel grant from Oxford University Press in the role of Deputy Editor for Human Reproduction and participates in a Data Safety and Monitoring Board as an independent methodologist in obstetrics studies in which she has no other role. M.v.W. is coordinating editor of Cochrane Fertility and Gynaecology. B.W.J.M. received an investigator grant from NHMRC (GNT1176437) and research funding from Merck KGaA. B.W.J.M. reports consultancy for Organon and Merck KGaA, and travel support from Merck KGaA. B.W.J.M. reports holding stocks of ObsEva. V.M. received research grants from Guerbet, Merck and Ferring and travel and speaker fees from Guerbet. The other authors do not report conflicts of interest., Trial Registration Number: International Clinical Trials Registry Platform No. NTR4746., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)
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- 2024
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12. Hysterosalpingo-foam sonography versus hysterosalpingography during fertility work-up: an economic evaluation alongside a randomized controlled trial.
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Kamphuis D, van Eekelen R, van Welie N, Dreyer K, van Rijswijk J, van Hooff MHA, de Bruin JP, Verhoeve HR, Mol F, van Baal WM, Traas MAF, van Peperstraten AM, Manger AP, Gianotten J, de Koning CH, Koning AMH, Bayram N, van der Ham DP, Vrouenraets FPJM, Kalafusova M, van de Laar BIG, Kaijser J, Lambeek AF, Meijer WJ, Broekmans FJM, Valkenburg O, van der Voet LF, van Disseldorp J, Lambers MJ, Tros R, Lambalk CB, Stoker J, van Wely M, Bossuyt PMM, Mol BWJ, and Mijatovic V
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- Humans, Female, Adult, Pregnancy, Cost-Benefit Analysis, Pregnancy Rate, Live Birth, Birth Rate, Hysterosalpingography methods, Hysterosalpingography economics, Infertility, Female therapy, Infertility, Female economics, Fallopian Tube Patency Tests methods, Fallopian Tube Patency Tests economics, Ultrasonography economics, Ultrasonography methods
- Abstract
Study Question: What are the costs and effects of tubal patency testing by hysterosalpingo-foam sonography (HyFoSy) compared to hysterosalpingography (HSG) in infertile women during the fertility work-up?, Summary Answer: During the fertility work-up, clinical management based on the test results of HyFoSy leads to slightly lower, though not statistically significant, live birth rates, at lower costs, compared to management based on HSG results., What Is Known Already: Traditionally, tubal patency testing during the fertility work-up is performed by HSG. The FOAM trial, formally a non-inferiority study, showed that management decisions based on the results of HyFoSy resulted in a comparable live birth rate at 12 months compared to HSG (46% versus 47%; difference -1.2%, 95% CI: -3.4% to 1.5%; P = 0.27). Compared to HSG, HyFoSy is associated with significantly less pain, it lacks ionizing radiation and exposure to iodinated contrast medium. Moreover, HyFoSy can be performed by a gynaecologist during a one-stop fertility work-up. To our knowledge, the costs of both strategies have never been compared., Study Design, Size, Duration: We performed an economic evaluation alongside the FOAM trial, a randomized multicenter study conducted in the Netherlands. Participating infertile women underwent, both HyFoSy and HSG, in a randomized order. The results of both tests were compared and women with discordant test results were randomly allocated to management based on the results of one of the tests. The follow-up period was twelve months., Participants/materials, Setting, Methods: We studied 1160 infertile women (18-41 years) scheduled for tubal patency testing. The primary outcome was ongoing pregnancy leading to live birth. The economic evaluation compared costs and effects of management based on either test within 12 months. We calculated incremental cost-effectiveness ratios (ICERs): the difference in total costs and chance of live birth. Data were analyzed using the intention to treat principle., Main Results and the Role of Chance: Between May 2015 and January 2019, 1026 of the 1160 women underwent both tubal tests and had data available: 747 women with concordant results (48% live births), 136 with inconclusive results (40% live births), and 143 with discordant results (41% had a live birth after management based on HyFoSy results versus 49% with live birth after management based on HSG results). When comparing the two strategies-management based on HyfoSy results versus HSG results-the estimated chance of live birth was 46% after HyFoSy versus 47% after HSG (difference -1.2%; 95% CI: -3.4% to 1.5%). For the procedures itself, HyFoSy cost €136 and HSG €280. When costs of additional fertility treatments were incorporated, the mean total costs per couple were €3307 for the HyFoSy strategy and €3427 for the HSG strategy (mean difference €-119; 95% CI: €-125 to €-114). So, while HyFoSy led to lower costs per couple, live birth rates were also slightly lower. The ICER was €10 042, meaning that by using HyFoSy instead of HSG we would save €10 042 per each additional live birth lost., Limitations, Reasons for Caution: When interpreting the results of this study, it needs to be considered that there was a considerable uncertainty around the ICER, and that the direct fertility enhancing effect of both tubal patency tests was not incorporated as women underwent both tubal patency tests in this study., Wider Implication of the Findings: Compared to clinical management based on HSG results, management guided by HyFoSy leads to slightly lower live birth rates (though not statistically significant) at lower costs, less pain, without ionizing radiation and iodinated contrast exposure. Further research on the comparison of the direct fertility-enhancing effect of both tubal patency tests is needed., Study Funding/competing Interest(s): FOAM trial was an investigator-initiated study, funded by ZonMw, a Dutch organization for Health Research and Development (project number 837001504). IQ Medical Ventures provided the ExEm®-FOAM kits free of charge. The funders had no role in study design, collection, analysis, and interpretation of the data. K.D. reports travel-and speakers fees from Guerbet and her department received research grants from Guerbet outside the submitted work. H.R.V. received consulting-and travel fee from Ferring. A.M.v.P. reports received consulting fee from DEKRA and fee for an expert meeting from Ferring, both outside the submitted work. C.H.d.K. received travel fee from Merck. F.J.M.B. received a grant from Merck and speakers fee from Besins Healthcare. F.J.M.B. is a member of the advisory board of Merck and Ferring. J.v.D. reported speakers fee from Ferring. J.S. reports a research agreement with Takeda and consultancy for Sanofi on MR of motility outside the submitted work. M.v.W. received a travel grant from Oxford Press in the role of deputy editor for Human Reproduction and participates in a DSMB as independent methodologist in obstetrics studies in which she has no other role. B.W.M. received an investigator grant from NHMRC GNT1176437. B.W.M. reports consultancy for ObsEva, Merck, Guerbet, iGenomix, and Merck KGaA and travel support from Merck KGaA. V.M. received research grants from Guerbet, Merck, and Ferring and travel and speakers fees from Guerbet. The other authors do not report conflicts of interest., Trial Registration Number: International Clinical Trials Registry Platform No. NTR4746., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)
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- 2024
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13. Cervical pessary versus vaginal progesterone in women with a singleton pregnancy, a short cervix, and no history of spontaneous preterm birth at less than 34 weeks' gestation: open label, multicentre, randomised, controlled trial.
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van Dijk CE, van Gils AL, van Zijl MD, Koullali B, van der Weide MC, van den Akker ES, Hermsen BJ, van Baal WM, Visser H, van Drongelen J, Vollebregt KC, Muller M, van der Made FW, Gordijn SJ, de Mooij YM, Oudijk MA, de Boer MA, Mol BW, Kazemier BM, and Pajkrt E
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- Adult, Female, Humans, Infant, Newborn, Pregnancy, Administration, Intravaginal, Cervix Uteri, Pessaries, Vagina, Premature Birth prevention & control, Progesterone
- Abstract
Objective: To compare the effectiveness of cervical pessary and vaginal progesterone in the prevention of adverse perinatal outcomes and preterm birth in pregnant women of singletons with no prior spontaneous preterm birth at less than 34 weeks' gestation and who have a short cervix of 35 mm or less., Design: Open label, multicentre, randomised, controlled trial., Setting: 20 hospitals and five obstetric ultrasound practices in the Netherlands., Participants: Women with a healthy singleton pregnancy and an asymptomatic short cervix of 35 mm or less between 18 and 22 weeks' gestation were eligible. Exclusion criteria were prior spontaneous preterm birth at less than 34 weeks, a cerclage in situ, maternal age of younger than 18 years, major congenital abnormalities, prior participation in this trial, vaginal blood loss, contractions, cervical length of less than 2 mm or cervical dilatation of 3 cm or more. Sample size was set at 628 participants., Interventions: 1:1 randomisation to an Arabin cervical pessary or vaginal progesterone 200 mg daily up to 36 weeks' of gestation or earlier in case of ruptured membranes, signs of infection, or preterm labour besides routine obstetric care., Main Outcome Measures: Primary outcome was a composite adverse perinatal outcome. Secondary outcomes were rates of (spontaneous) preterm birth at less than 28, 32, 34, and 37 weeks. A predefined subgroup analysis was planned for cervical length of 25 mm or less., Results: From 1 July 2014 to 31 March 2022, 635 participants were randomly assigned to pessary (n=315) or to progesterone (n=320). 612 were included in the intention to treat analysis. The composite adverse perinatal outcome occurred in 19 (6%) of 303 participants with a pessary versus 17 (6%) of 309 in the progesterone group (crude relative risk 1.1 (95% confidence interval (CI) 0.60 to 2.2)). The rates of spontaneous preterm birth were not significantly different between groups. In the subgroup of cervical length of 25 mm or less, spontaneous preterm birth at less than 28 weeks occurred more often after pessary than after progesterone (10/62 (16%) v 3/69 (4%), relative risk 3.7 (95% CI 1.1 to 12.9)) and adverse perinatal outcomes seemed more frequent in the pessary group (15/62 (24%) v 8/69 (12%), relative risk 2.1 (0.95 to 4.6))., Conclusions: In women with a singleton pregnancy with no prior spontaneous preterm birth at less than 34 weeks' gestation and with a midtrimester short cervix of 35 mm or less, pessary is not better than vaginal progesterone. In the subgroup of a cervical length of 25 mm or less, a pessary seemed less effective in preventing adverse outcomes. Overall, for women with single baby pregnancies, a short cervix, and no prior spontaneous preterm birth less than 34 weeks' gestation, superiority of a cervical pessary compared with vaginal progesterone to prevent preterm birth and consecutive adverse outcomes could not be proven., Trial Registration: International Clinical Trial Registry Platform (ICTRP, EUCTR2013-002884-24-NL)., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest and declare: BWJM declared support by a NHMRC Investigator grant (GNT1176437). BWM reports consultancy, research funding and travel support from Merck. EP and MAO declared participation on the board of the Research foundation ‘Stichting Stoptevroegbevallen’ that supported this study. EP, MAO and SJG received several grants with the purpose of scientific research in the field op preterm birth and fetal growth restriction. All other authors declare no support from any organisation for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
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- 2024
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14. DNA methylation testing for endometrial cancer detection in urine, cervicovaginal self-samples and cervical scrapes.
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Wever BMM, van den Helder R, van Splunter AP, van Gent MDJM, Kasius JC, Trum JW, Verhoeve HR, van Baal WM, Hulbert A, Verhoef L, Heideman DAM, Lissenberg-Witte BI, van Trommel NE, Steenbergen RDM, and Bleeker MCG
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- Female, Humans, DNA Methylation, Cervix Uteri pathology, Biopsy, Uterine Cervical Neoplasms diagnosis, Uterine Cervical Neoplasms genetics, Uterine Cervical Neoplasms pathology, Endometrial Neoplasms diagnosis, Endometrial Neoplasms genetics, Uterine Cervical Dysplasia diagnosis, Papillomavirus Infections diagnosis
- Abstract
Endometrial cancer incidence is rising and current diagnostics often require invasive biopsy procedures. DNA methylation marker analysis of minimally- and non-invasive sample types could provide an easy-to-apply and patient-friendly alternative to determine cancer risk. Here, we compared the performance of DNA methylation markers to detect endometrial cancer in urine, cervicovaginal self-samples and clinician-taken cervical scrapes. Paired samples were collected from 103 patients diagnosed with stage I to IV endometrial cancer. Urine and self-samples were collected at home. All samples were tested for nine DNA methylation markers using quantitative methylation-specific PCR. Methylation levels measured in endometrial cancer patients were compared to unpaired samples of 317 healthy controls. Diagnostic performances were evaluated by univariable and multivariable logistic regression analysis, followed by leave-one-out cross-validation. Each methylation marker showed significantly higher methylation levels in all sample types of endometrial cancer patients compared to healthy controls (P < .01). Optimal three-marker combinations demonstrated excellent diagnostic performances with area under the receiver operating curve values of 0.95 (95% CI: 0.92-0.98), 0.94 (0.90-0.97) and 0.97 (0.96-0.99), for endometrial cancer detection in urine, self-samples and scrapes, respectively. Sensitivities ranged from 89% to 93% at specificities of 90% to 92%. Virtually equal performances were obtained after cross-validation and excellent diagnostic performances were maintained for stage I endometrial cancer detection. Our study shows the value of methylation analysis in patient-friendly sample types for endometrial cancer detection of all stages. This approach has great potential to screen patient populations at risk for endometrial cancer., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
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- 2023
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15. Clinical outcomes of uninterrupted embryo culture with or without time-lapse-based embryo selection versus interrupted standard culture (SelecTIMO): a three-armed, multicentre, double-blind, randomised controlled trial.
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Kieslinger DC, Vergouw CG, Ramos L, Arends B, Curfs MHJM, Slappendel E, Kostelijk EH, Pieters MHEC, Consten D, Verhoeven MO, Besselink DE, Broekmans F, Cohlen BJ, Smeenk JMJ, Mastenbroek S, de Koning CH, van Kasteren YM, Moll E, van Disseldorp J, Brinkhuis EA, Kuijper EAM, van Baal WM, van Weering HGI, van der Linden PJQ, Gerards MH, Bossuyt PM, van Wely M, and Lambalk CB
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- Pregnancy, Male, Female, Humans, Time-Lapse Imaging methods, Pregnancy Rate, Reproductive Techniques, Assisted, Semen, Fertilization in Vitro
- Abstract
Background: Time-lapse monitoring is increasingly used in fertility laboratories to culture and select embryos for transfer. This method is offered to couples with the promise of improving pregnancy chances, even though there is currently insufficient evidence for superior clinical results. We aimed to evaluate whether a potential improvement by time-lapse monitoring is caused by the time-lapse-based embryo selection method itself or the uninterrupted culture environment that is part of the system., Methods: In this three-armed, multicentre, double-blind, randomised controlled trial, couples undergoing in-vitro fertilisation or intracytoplasmic sperm injection were recruited from 15 fertility clinics in the Netherlands and randomly assigned using a web-based, computerised randomisation service to one of three groups. Couples and physicians were masked to treatment group, but embryologists and laboratory technicians could not be. The time-lapse early embryo viability assessment (EEVA; TLE) group received embryo selection based on the EEVA time-lapse selection method and uninterrupted culture. The time-lapse routine (TLR) group received routine embryo selection and uninterrupted culture. The control group received routine embryo selection and interrupted culture. The co-primary endpoints were the cumulative ongoing pregnancy rate within 12 months in all women and the ongoing pregnancy rate after fresh single embryo transfer in a good prognosis population. Analysis was by intention to treat. This trial is registered on the ICTRP Search Portal, NTR5423, and is closed to new participants., Findings: 1731 couples were randomly assigned between June 15, 2017, and March 31, 2020 (577 to the TLE group, 579 to the TLR group, and 575 to the control group). The 12-month cumulative ongoing pregnancy rate did not differ significantly between the three groups: 50·8% (293 of 577) in the TLE group, 50·9% (295 of 579) in the TLR group, and 49·4% (284 of 575) in the control group (p=0·85). The ongoing pregnancy rates after fresh single embryo transfer in a good prognosis population were 38·2% (125 of 327) in the TLE group, 36·8% (119 of 323) in the TLR group, and 37·8% (123 of 325) in the control group (p=0·90). Ten serious adverse events were reported (five TLE, four TLR, and one in the control group), which were not related to study procedures., Interpretation: Neither time-lapse-based embryo selection using the EEVA test nor uninterrupted culture conditions in a time-lapse incubator improved clinical outcomes compared with routine methods. Widespread application of time-lapse monitoring for fertility treatments with the promise of improved results should be questioned., Funding: Health Care Efficiency Research programme from Netherlands Organisation for Health Research and Development and Merck., Competing Interests: Declaration of interests DCK received the Fertility Society of Australia exchange award. MHJMC reports an unrestricted grant for implementing Value Based Healthcare paid to their institution and a personal speakers fee from Merck (Netherlands). FB reports a research support grant from Merck (Netherlands), Health Care Efficiency Research program grant from the Netherlands Organisation for Health Research and Development, speaker fees and scientific dinner symposium from Besins Healthcare Monaco, and is a member of the advisory board for Merck (Netherlands) and Ferring (Netherlands). CHdK reports a donation from Merck (Netherlands) for the European Society of Human Reproduction and Embryology annual meeting 2022 in Milan. MvW is coordinating editor of the Cochrane Gynecology and Fertility Group. CBL is Editor-In-Chief for Human Reproduction. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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16. Psychological impact of referral to an oncology hospital on patients with an ovarian mass.
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Lof P, Engelhardt EG, van Gent MDJM, Mom CH, Rosier-van Dunné FMF, van Baal WM, Verhoeve HR, Hermsen BBJ, Verbruggen MB, Hemelaar M, van de Swaluw JMG, Knipscheer HC, Huirne JAF, Westenberg SM, van Driel WJ, Bleiker EMA, Amant F, and Lok CAR
- Abstract
Objectives: In patients with an ovarian mass, a risk of malignancy assessment is used to decide whether referral to an oncology hospital is indicated. Risk assessment strategies do not perform optimally, resulting in either referral of patients with a benign mass or patients with a malignant mass not being referred. This process may affect the psychological well-being of patients. We evaluated cancer-specific distress during work-up for an ovarian mass, and patients' perceptions during work-up, referral, and treatment., Methods: Patients with an ovarian mass scheduled for surgery were enrolled. Using questionnaires we measured (1) cancer-specific distress using the cancer worry scale, (2) patients' preferences regarding referral (evaluated pre-operatively), and (3) patients' experiences with work-up and treatment (evaluated post-operatively). A cancer worry scale score of ≥14 was considered as clinically significant cancer-specific distress., Results: A total of 417 patients were included, of whom 220 (53%) were treated at a general hospital and 197 (47%) at an oncology hospital. Overall, 57% had a cancer worry scale score of ≥14 and this was higher in referred patients (69%) than in patients treated at a general hospital (43%). 53% of the patients stated that the cancer risk should not be higher than 25% to undergo surgery at a general hospital. 96% of all patients were satisfied with the overall work-up and treatment. No difference in satisfaction was observed between patients correctly (not) referred and patients incorrectly (not) referred., Conclusions: Relatively many patients with an ovarian mass experienced high cancer-specific distress during work-up. Nevertheless, patients were satisfied with the treatment, regardless of the final diagnosis and the location of treatment. Moreover, patients preferred to be referred even if there was only a relatively low probability of having ovarian cancer. Patients' preferences should be taken into account when deciding on optimal cut-offs for risk assessment strategies., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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17. Clinical Regression of High-Grade Cervical Intraepithelial Neoplasia Is Associated With Absence of FAM19A4/miR124-2 DNA Methylation (CONCERVE Study).
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Kremer WW, Dick S, Heideman DAM, Steenbergen RDM, Bleeker MCG, Verhoeve HR, van Baal WM, van Trommel N, Kenter GG, Meijer CJLM, and Berkhof J
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- Adult, DNA Methylation, Early Detection of Cancer, Female, Genotype, Humans, Longitudinal Studies, Middle Aged, Papillomaviridae, Young Adult, Cytokines genetics, MicroRNAs genetics, Papillomavirus Infections complications, Papillomavirus Infections genetics, Uterine Cervical Neoplasms diagnosis, Uterine Cervical Neoplasms genetics, Uterine Cervical Neoplasms surgery, Uterine Cervical Dysplasia genetics, Uterine Cervical Dysplasia pathology, Uterine Cervical Dysplasia surgery
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Purpose: Cervical screening can prevent cancer by detection and treatment of cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3). Screening also results in considerable overtreatment because many CIN2/3 lesions show spontaneous regression when left untreated. In this multicenter longitudinal cohort study of women with untreated CIN2/3, the prognostic value of FAM19A4/miR124-2 methylation was evaluated for clinical regression., Patients and Methods: Women with CIN2/3 were prospectively followed for 24 months. Surgical excision was replaced by a wait-and-see policy. FAM19A4/miR124-2 methylation was evaluated on all clinician-collected samples and self-collected samples collected at baseline. Every 6 months, human papillomavirus (HPV) testing and cytology were conducted on a clinician-collected sample, and a colposcopic examination was performed by a gynecologist to exclude progression. At the final study visit, two biopsies were taken. Clinical regression was defined as histologically confirmed absence of CIN2+ or an HPV-negative clinician-collected sample with normal cytology. Regression incidences were estimated using the Kaplan-Meier method., Results: One hundred fourteen women (median age, 30 years; range, 20-53 years) were included, 80 of whom were diagnosed with CIN2 and 34 with CIN3. During the study, 65.8% of women (75/114) did not receive surgical treatment. Women with a negative FAM19A4/miR124-2 result on the baseline clinician-collected sample showed more clinical regression (74.7%) than women with a positive methylation result (51.4%, P = .013). Regression in women with a negative FAM19A4/miR124-2 methylation test was highest when cytology was atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion (88.4%) or HPV16 was negative (85.1%)., Conclusion: Most women with untreated CIN2/3 and a negative baseline FAM19A4/miR124-2 methylation test showed clinical regression. Methylation, in combination with cytology or HPV genotyping, can be used to support a wait-and-see policy in women with CIN2/3.
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- 2022
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18. Can serum human epididymis protein 4 (HE4) support the decision to refer a patient with an ovarian mass to an oncology hospital?
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Lof P, van de Vrie R, Korse CM, van Gent MDJM, Mom CH, Rosier-van Dunné FMF, van Baal WM, Verhoeve HR, Hermsen BBJ, Verbruggen MB, Hemelaar M, van de Swaluw AMG, Knipscheer HC, Huirne JAF, Westenberg SM, van der Noort V, Amant F, van den Broek D, and Lok CAR
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- Algorithms, Biomarkers, Tumor, CA-125 Antigen, Female, Hospitals, Humans, Ovarian Neoplasms pathology, Proteins metabolism, WAP Four-Disulfide Core Domain Protein 2 analysis
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Introduction: The value of serum human epididymis protein 4 (HE4) in guiding referral decisions in patients with an ovarian mass remains unclear, because the majority of studies investigating HE4 were performed in oncology hospitals. However, the decision to refer is made at general hospitals with a low ovarian cancer prevalence. We assessed accuracies of HE4 in differentiating benign or borderline from malignant tumors in patients presenting with an ovarian mass at general hospitals., Method: Patients with an ovarian mass were prospectively included between 2017 and 2021 in nine general hospitals. HE4 and CA125 were preoperatively measured and the risk of malignancy index (RMI) was calculated. Histological diagnosis was the reference standard., Results: We included 316 patients, of whom 195 had a benign, 39 had a borderline and 82 had a malignant ovarian mass. HE4 had the highest AUC of 0.80 (95%CI 0.74-0.86), followed by RMI (0.71, 95%CI 0.64-0.78) and CA125 (0.69, 95%CI 0.62-0.75). Clinical setting significantly influenced biomarker performances. Applying age-dependent cut-off values for HE4 resulted in a better performance than one cut-off. Addition of HE4 to RMI resulted in a 32% decrease of unnecessary referred patients, while the number of correctly referred patients remained the same., Conclusion: HE4 is superior to RMI in predicting malignancy in patients with an ovarian mass from general hospitals. The addition of HE4 to the RMI improved HE4 alone. Although, there is still room for improvement, HE4 can guide referral decisions in patients with an ovarian mass to an oncology hospital., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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19. Can hysterosalpingo-foam sonography replace hysterosalpingography as first-choice tubal patency test? A randomized non-inferiority trial.
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van Welie N, van Rijswijk J, Dreyer K, van Hooff MHA, de Bruin JP, Verhoeve HR, Mol F, van Baal WM, Traas MAF, van Peperstraten AM, Manger AP, Gianotten J, de Koning CH, Koning AMH, Bayram N, van der Ham DP, Vrouenraets FPJM, Kalafusova M, van de Laar BIG, Kaijser J, Lambeek AF, Meijer WJ, Broekmans FJM, Valkenburg O, van der Voet LF, van Disseldorp J, Lambers MJ, Tros R, Lambalk CB, Stoker J, van Wely M, Bossuyt PMM, Mol BWJ, and Mijatovic V
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- Adolescent, Adult, Female, Humans, Male, Pain, Pregnancy, Pregnancy Rate, Prospective Studies, Young Adult, Hysterosalpingography adverse effects, Infertility, Female diagnostic imaging, Infertility, Female therapy
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Study Question: Does hysterosalpingo-foam sonography (HyFoSy) lead to similar pregnancy outcomes, compared with hysterosalpingography (HSG), as first-choice tubal patency test in infertile couples?, Summary Answer: HyFoSy and HSG produce similar findings in a majority of patients and clinical management based on the results of either HyFoSy or HSG, leads to comparable pregnancy outcomes. HyFoSy is experienced as significantly less painful., What Is Known Already: Traditionally, tubal patency testing during fertility work-up is performed by HSG. HyFoSy is an alternative imaging technique lacking ionizing radiation and iodinated contrast medium exposure which is less expensive than HSG. Globally, there is a shift towards the use of office-based diagnostic methods, such as HyFoSy., Study Design, Size, Duration: This multicentre, prospective, comparative study with a randomized design was conducted in 26 hospitals in The Netherlands. Participating women underwent both HyFoSy and HSG in randomized order. In case of discordant results, women were randomly allocated to either a management strategy based on HyFoSy or one based on HSG., Participants/materials, Setting, Methods: We included infertile women between 18 and 41 years old who were scheduled for tubal patency testing during their fertility work-up. Women with anovulatory cycles not responding to ovulation induction, endometriosis, severe male infertility or a known iodine contrast allergy were excluded. The primary outcome for the comparison of the HyFoSy- and HSG-based strategies was ongoing pregnancy leading to live birth within 12 months after inclusion in an intention-to-treat analysis., Main Results and the Role of Chance: Between May 2015 and January 2019, 1026 women underwent HyFoSy and HSG. HyFoSy was inconclusive in 97 of them (9.5%), HSG was inconclusive in 30 (2.9%) and both were inconclusive in 9 (0.9%). In 747 women (73%) conclusive tests results were concordant. Of the 143/1026 (14%) with discordant results, 105 were randomized to clinical management based on the results of either HyFoSy or HSG. In this group, 22 of the 54 women (41%) allocated to management based on HyFoSy and 25 of 51 women (49%) allocated to management based on HSG had an ongoing pregnancy leading to live birth (Difference -8%; 95% CI: -27% to 10%). In total, clinical management based on the results of HyFoSy was estimated to lead to a live birth in 474 of 1026 women (46%) versus 486 of 1026 (47%) for management based on HSG (Difference -1.2%; 95% CI: -3.4% to 1.5%). Given the pre-defined margin of -2%, statistically significant non-inferiority of HyFoSy relative to HSG could not be demonstrated (P = 0.27). The mean pain score for HyFoSy on the 1-10 Visual Analogue Scale (VAS) was 3.1 (SD 2.2) and the mean VAS pain score for HSG was 5.4 (SD 2.5; P for difference < 0.001)., Limitations, Reasons for Caution: Since all women underwent both tubal patency tests, no conclusions on a direct therapeutic effect of tubal flushing could be drawn., Wider Implications of the Findings: HyFoSy or HSG produce similar tubal pathology findings in a majority of infertile couples and, where they differ, a difference in findings does not lead to substantial difference in pregnancy outcome, while HyFoSy is associated with significantly less pain., Study Funding/competing Interest(s): The FOAM study was an investigator-initiated study funded by ZonMw, The Netherlands organization for Health Research and Development (project number 837001504). ZonMw funded the whole project. IQ Medical Ventures provided the ExEm-foam® kits free of charge. The funders had no role in study design, collection, analysis and interpretation of the data. K.D. reports travel and speaker fees from Guerbet. F.J.M.B. reports personal fees as a member of the external advisory board for Merck Serono, The Netherlands, and a research support grant from Merck Serono, outside the submitted work. C.B.L. reports speakers' fee from Ferring in the past, and his department receives research grants from Ferring, Merck and Guerbet. J.S. reports a research agreement with Takeda on MR of motility outside the submitted work. M.V.W. reports leading The Netherlands Satellite of the Cochrane Gynaecology and Fertility Group. B.W.J.M. is supported by an NHMRC Investigator grant (GNT1176437). B.W.J.M. reports consultancy for Guerbet and research funding from Merck and Guerbet. V.M. reports non-financial support from IQ medicals ventures, during the conduct of the study; grants and personal fees from Guerbet, outside the submitted work. The other authors do not report conflicts of interest., Trial Registration Number: NTR4746/NL4587 (https://www.trialregister.nl)., Trial Registration Date: 19 August 2014., Date of First Patient’s Enrolment: 7 May 2015., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)
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- 2022
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20. Single- versus double-layer closure of the caesarean (uterine) scar in the prevention of gynaecological symptoms in relation to niche development - the 2Close study: a multicentre randomised controlled trial.
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Stegwee SI, Jordans IPM, van der Voet LF, Bongers MY, de Groot CJM, Lambalk CB, de Leeuw RA, Hehenkamp WJK, van de Ven PM, Bosmans JE, Pajkrt E, Bakkum EA, Radder CM, Hemelaar M, van Baal WM, Visser H, van Laar JOEH, van Vliet HAAM, Rijnders RJP, Sueters M, Janssen CAH, Hermes W, Feitsma AH, Kapiteijn K, Scheepers HCJ, Langenveld J, de Boer K, Coppus SFPJ, Schippers DH, Oei ALM, Kaplan M, Papatsonis DNM, de Vleeschouwer LHM, van Beek E, Bekker MN, Huisjes AJM, Meijer WJ, Deurloo KL, Boormans EMA, van Eijndhoven HWF, and Huirne JAF
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- Cicatrix diagnostic imaging, Cicatrix etiology, Double-Blind Method, Dysmenorrhea etiology, Endosonography, Female, Fertility, Humans, Menstruation, Obstetric Labor Complications etiology, Pregnancy, Quality of Life, Randomized Controlled Trials as Topic, Sexuality, Uterus diagnostic imaging, Cesarean Section methods, Metrorrhagia etiology, Suture Techniques adverse effects, Uterus surgery
- Abstract
Background: Double-layer compared to single-layer closure of the uterus after a caesarean section (CS) leads to a thicker myometrial layer at the site of the CS scar, also called residual myometrium thickness (RMT). It possibly decreases the development of a niche, which is an interruption of the myometrium at the site of the uterine scar. Thin RMT and a niche are associated with gynaecological symptoms, obstetric complications in a subsequent pregnancy and delivery and possibly with subfertility., Methods: Women undergoing a first CS regardless of the gestational age will be asked to participate in this multicentre, double blinded randomised controlled trial (RCT). They will be randomised to single-layer closure or double-layer closure of the uterine incision. Single-layer closure (control group) is performed with a continuous running, unlocked suture, with or without endometrial saving technique. Double-layer closure (intervention group) is performed with the first layer in a continuous unlocked suture including the endometrial layer and the second layer is also continuous unlocked and imbricates the first. The primary outcome is the reported number of days with postmenstrual spotting during one menstrual cycle nine months after CS. Secondary outcomes include surgical data, ultrasound evaluation at three months, menstrual pattern, dysmenorrhea, quality of life, and sexual function at nine months. Structured transvaginal ultrasound (TVUS) evaluation is performed to assess the uterine scar and if necessary saline infusion sonohysterography (SIS) or gel instillation sonohysterography (GIS) will be added to the examination. Women and ultrasound examiners will be blinded for allocation. Reproductive outcomes at three years follow-up including fertility, mode of delivery and complications in subsequent deliveries will be studied as well. Analyses will be performed by intention to treat. 2290 women have to be randomised to show a reduction of 15% in the mean number of spotting days. Additionally, a cost-effectiveness analysis will be performed from a societal perspective., Discussion: This RCT will provide insight in the outcomes of single- compared to double-layer closure technique after CS, including postmenstrual spotting and subfertility in relation to niche development measured by ultrasound., Trial Registration: Dutch Trial Register ( NTR5480 ). Registered 29 October 2015.
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- 2019
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21. Electronic Health Program to Empower Patients in Returning to Normal Activities After General Surgical and Gynecological Procedures: Intervention Mapping as a Useful Method for Further Development.
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den Bakker CM, Schaafsma FG, van der Meij E, Meijerink WJ, van den Heuvel B, Baan AH, Davids PH, Scholten PC, van der Meij S, van Baal WM, van Dalsen AD, Lips DJ, van der Steeg JW, Leclercq WK, Geomini PM, Consten EC, Schraffordt Koops SE, de Castro SM, van Kesteren PJ, Cense HA, Stockmann HB, Ten Cate AD, Bonjer HJ, Huirne JA, and Anema JR
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- Electronics, Female, Gynecologic Surgical Procedures methods, Humans, Gynecologic Surgical Procedures instrumentation, Health Promotion methods, Patient Reported Outcome Measures, Telemedicine methods
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Background: Support for guiding and monitoring postoperative recovery and resumption of activities is usually not provided to patients after discharge from the hospital. Therefore, a perioperative electronic health (eHealth) intervention ("ikherstel" intervention or "I recover" intervention) was developed to empower gynecological patients during the perioperative period. This eHealth intervention requires a need for further development for patients who will undergo various types of general surgical and gynecological procedures., Objective: This study aimed to further develop the "ikherstel" eHealth intervention using Intervention Mapping (IM) to fit a broader patient population., Methods: The IM protocol was used to guide further development of the "ikherstel" intervention. First, patients' needs were identified using (1) the information of a process evaluation of the earlier performed "ikherstel" study, (2) a review of the literature, (3) a survey study, and (4) focus group discussions (FGDs) among stakeholders. Next, program outcomes and change objectives were defined. Third, behavior change theories and practical tools were selected for the intervention program. Finally, an implementation and evaluation plan was developed., Results: The outcome for an eHealth intervention tool for patients recovering from abdominal general surgical and gynecological procedures was redefined as "achieving earlier recovery including return to normal activities and work." The Attitude-Social Influence-Self-Efficacy model was used as a theoretical framework to transform personal and external determinants into change objectives of personal behavior. The knowledge gathered by needs assessment and using the theoretical framework in the preparatory steps of the IM protocol resulted in additional tools. A mobile app, an activity tracker, and an electronic consultation (eConsult) will be incorporated in the further developed eHealth intervention. This intervention will be evaluated in a multicenter, single-blinded randomized controlled trial with 18 departments in 11 participating hospitals in the Netherlands., Conclusions: The intervention is extended to patients undergoing general surgical procedures and for malignant indications. New intervention tools such as a mobile app, an activity tracker, and an eConsult were developed., Trial Registration: Netherlands Trial Registry NTR5686; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5686., (©Chantal M den Bakker, Frederieke G Schaafsma, Eva van der Meij, Wilhelmus JHJ Meijerink, Baukje van den Heuvel, Astrid H Baan, Paul HP Davids, Petrus C Scholten, Suzan van der Meij, W Marchien van Baal, Annette D van Dalsen, Daniel J Lips, Jan Willem van der Steeg, Wouter KG Leclercq, Peggy MAJ Geomini, Esther CJ Consten, Steven E Schraffordt Koops, Steve MM de Castro, Paul JM van Kesteren, Huib A Cense, Hein BAC Stockmann, A Dorien ten Cate, Hendrik J Bonjer, Judith AF Huirne, Johannes R Anema. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 06.02.2019.)
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- 2019
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22. Pessary or Progesterone to Prevent Preterm delivery in women with short cervical length: the Quadruple P randomised controlled trial.
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van Zijl MD, Koullali B, Naaktgeboren CA, Schuit E, Bekedam DJ, Moll E, Oudijk MA, van Baal WM, de Boer MA, Visser H, van Drongelen J, van de Made FW, Vollebregt KC, Muller MA, Bekker MN, Brons JTJ, Sueters M, Langenveld J, Franssen MT, Schuitemaker NW, van Beek E, Scheepers HCJ, de Boer K, Tepe EM, Huisjes AJM, Hooker AB, Verheijen ECJ, Papatsonis DN, Mol BWJ, Kazemier BM, and Pajkrt E
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- Administration, Intravaginal, Adolescent, Adult, Cervical Length Measurement, Clinical Protocols, Female, Humans, Pregnancy, Pregnancy Outcome, Premature Birth etiology, Treatment Outcome, Uterine Cervical Diseases diagnostic imaging, Uterine Cervical Diseases pathology, Young Adult, Cervix Uteri pathology, Pessaries, Premature Birth prevention & control, Progesterone administration & dosage, Progestins administration & dosage, Uterine Cervical Diseases complications
- Abstract
Background: Preterm birth is in quantity and in severity the most important topic in obstetric care in the developed world. Progestogens and cervical pessaries have been studied as potential preventive treatments with conflicting results. So far, no study has compared both treatments., Methods/design: The Quadruple P study aims to compare the efficacy of vaginal progesterone and cervical pessary in the prevention of adverse perinatal outcome associated with preterm birth in asymptomatic women with a short cervix, in singleton and multiple pregnancies separately. It is a nationwide open-label multicentre randomized clinical trial (RCT) with a superiority design and will be accompanied by an economic analysis. Pregnant women undergoing the routine anomaly scan will be offered cervical length measurement between 18 and 22 weeks in a singleton and at 16-22 weeks in a multiple pregnancy. Women with a short cervix, defined as less than, or equal to 35 mm in a singleton and less than 38 mm in a multiple pregnancy, will be invited to participate in the study. Eligible women will be randomly allocated to receive either progesterone or a cervical pessary. Following randomization, the silicone cervical pessary will be placed during vaginal examination or 200 mg progesterone capsules will be daily self-administered vaginally. Both interventions will be continued until 36 weeks gestation or until delivery, whichever comes first. Primary outcome will be composite adverse perinatal outcome of perinatal mortality and perinatal morbidity including bronchopulmonary dysplasia, intraventricular haemorrhage grade III and IV, periventricular leukomalacia higher than grade I, necrotizing enterocolitis higher than stage I, Retinopathy of prematurity (ROP) or culture proven sepsis. These outcomes will be measured up until 10 weeks after the expected due date. Secondary outcomes will be, among others, time to delivery, preterm birth rate before 28, 32, 34 and 37 weeks, admission to neonatal intensive care unit, maternal morbidity, maternal admission days for threatened preterm labour and costs., Discussion: This trial will provide evidence on whether vaginal progesterone or a cervical pessary is more effective in decreasing adverse perinatal outcome in both singletons and multiples., Trial Registration: Trial registration number: NTR 4414 . Date of registration January 29th 2014.
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- 2017
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23. Good performance of p16/ki-67 dual-stained cytology for surveillance of women treated for high-grade CIN.
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Polman NJ, Uijterwaal MH, Witte BI, Berkhof J, van Kemenade FJ, Spruijt JW, van Baal WM, Graziosi PG, van Dijken DK, Verheijen RH, Helmerhorst TJ, Steenbergen RD, Heideman DA, Ridder R, Snijders PJ, and Meijer CJ
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- Adult, Colposcopy methods, Cytodiagnosis methods, Early Detection of Cancer methods, Female, Humans, Middle Aged, Papillomaviridae, Papillomavirus Infections metabolism, Papillomavirus Infections pathology, Pregnancy, Prospective Studies, Sensitivity and Specificity, Uterine Cervical Neoplasms virology, Young Adult, Uterine Cervical Dysplasia virology, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Ki-67 Antigen metabolism, Uterine Cervical Neoplasms metabolism, Uterine Cervical Neoplasms pathology, Uterine Cervical Dysplasia metabolism, Uterine Cervical Dysplasia pathology
- Abstract
Women treated for high-grade cervical intraepithelial neoplasia (CIN) are at risk of recurrent CIN Grade 2 or worse (rCIN2+). Currently, posttreatment monitoring is performed using cytology or cytology/high-risk (hr)HPV cotesting. This study aimed to evaluate the performance of p16/Ki-67 dual-stained cytology (p16/Ki-67) for posttreatment monitoring. Three hundred and twenty-three women treated for high-grade CIN in the SIMONATH study underwent close surveillance by cytology, hrHPV and DNA methylation marker testing up to 12 months posttreatment. Histological endpoints were ascertained by colposcopy with biopsy at 6 and/or 12 months. p16/Ki-67 dual-staining was performed on residual liquid-based cytology samples obtained at, or shortly before biopsy collection. Clinical performance estimates of cytology, hrHPV, p16/Ki-67 testing and combinations thereof for the detection of rCIN2+ were determined and compared to each other. Sensitivity of p16/Ki-67 for rCIN2+ (69.2%) was nonsignificantly lower than that of cytology (82.1%; ratio 0.84, 95% CI: 0.71-1.01), but significantly lower than that of hrHPV testing (84.6%; ratio 0.82, 95% CI: 0.68-0.99). Specificity of p16/Ki-67 for rCIN2+ (90.4%) was significantly higher compared to both cytology (70.8%; ratio 1.28, 95% CI: 1.19-1.37) and hrHPV testing (76.2%; ratio 1.19, 95% CI: 1.12-1.26). Overall, hrHPV testing showed very high sensitivity, along with a good specificity. When considering cotesting, combined p16/Ki-67/hrHPV testing showed rCIN2+ sensitivity comparable to cytology/hrHPV cotesting (87.2% vs. 89.7%; ratio 0.97, 95% CI: 0.92-1.03), but with significantly increased specificity (74.2% vs. 58.1%; ratio 1.28, 95% CI: 1.19-1.38). Thus, when considered in combination with hrHPV, p16/Ki-67 might be an attractive approach for surveillance of women treated for high-grade CIN., (© 2016 UICC.)
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- 2017
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24. Word catheter and marsupialisation in women with a cyst or abscess of the Bartholin gland (WoMan-trial): a randomised clinical trial.
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Kroese JA, van der Velde M, Morssink LP, Zafarmand MH, Geomini P, van Kesteren P, Radder CM, van der Voet LF, Roovers J, Graziosi G, van Baal WM, van Bavel J, Catshoek R, Klinkert ER, Huirne J, Clark TJ, Mol B, and Reesink-Peters N
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- Adult, Catheterization methods, Female, Humans, Middle Aged, Treatment Outcome, Abscess surgery, Bartholin's Glands surgery, Catheterization instrumentation, Catheters, Cysts surgery, Gynecologic Surgical Procedures methods
- Abstract
Objective: To compare recurrence of a cyst or abscess of the Bartholin gland after surgical treatment using a Word catheter or marsupialisation., Design: Multicentre, open-label, randomised controlled trial., Setting: Eighteen hospitals in the Netherlands and one hospital in England., Population: Women with a symptomatic cyst or abscess of the Bartholin gland., Methods: Women were randomised to treatment with Word catheter or marsupialisation., Main Outcome Measures: The primary outcome was recurrence of the cyst or abscess within 1 year of treatment. The secondary outcomes included pain during and after treatment (measured on a 10-point scale), use of analgesics, and time from diagnosis to treatment. Analysis was by intention-to-treat. To assess whether marsupialisation would reduce the recurrence rate by 5% (from 20 to 15%) we needed to include 160 women (alpha error 0.05, beta error 0.2)., Results: One hundred and sixty-one women were randomly allocated to treatment by Word catheter (n = 82) or marsupialisation (n = 79) between August 2010 and May 2014. Baseline characteristics were comparable. Recurrence occurred in 10 women (12%) allocated to Word catheter versus eight women (10%) allocated to marsupialisation: relative risk (RR) 1.1, 95% confidence interval (CI) 0.64-1.91; P = 0.70. Pain scores after treatment were also comparable. In the first 24 hours after treatment, 33% used analgesics in the Word catheter group versus 74% in the marsupialisation group (P < 0.001). Time from diagnosis to treatment was 1 hour for placement of Word catheter versus 4 hours for marsupialisation (P = 0.001)., Conclusions: In women with an abscess or cyst of the Bartholin gland, treatment with Word catheter and marsupialisation results in comparable recurrence rates., Tweetable Abstract: Comparable recurrence rates for treatment of Bartholinic abscess/cyst with Word catheter and marsupialisation., (© 2016 Royal College of Obstetricians and Gynaecologists.)
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- 2017
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25. Substitution of Usual Perioperative Care by eHealth to Enhance Postoperative Recovery in Patients Undergoing General Surgical or Gynecological Procedures: Study Protocol of a Randomized Controlled Trial.
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van der Meij E, Huirne JA, Bouwsma EV, van Dongen JM, Terwee CB, van de Ven PM, den Bakker CM, van der Meij S, van Baal WM, Leclercq WK, Geomini PM, Consten EC, Schraffordt Koops SE, van Kesteren PJ, Stockmann HB, Ten Cate AD, Davids PH, Scholten PC, van den Heuvel B, Schaafsma FG, Meijerink WJ, Bonjer HJ, and Anema JR
- Abstract
Background: Due to the strong reduction in the length of hospital stays in the last decade, the period of in-hospital postoperative care is limited. After discharge from the hospital, guidance and monitoring on recovery and resumption of (work) activities are usually not provided. As a consequence, return to normal activities and work after surgery is hampered, leading to a lower quality of life and higher costs due to productivity loss and increased health care consumption., Objective: With this study we aim to evaluate whether an eHealth care program can improve perioperative health care in patients undergoing commonly applied abdominal surgical procedures, leading to accelerated recovery and to a reduction in costs in comparison to usual care., Methods: This is a multicenter randomized, single-blinded, controlled trial. At least 308 patients between 18 and 75 years old who are on the waiting list for a laparoscopic cholecystectomy, inguinal hernia surgery, or laparoscopic adnexal surgery for a benign indication will be included. Patients will be randomized to an intervention or control group. The intervention group will have access to an innovative, perioperative eHealth care program. This intervention program consists of a website, mobile phone app, and activity tracker. It aims to improve patient self-management and empowerment by providing guidance to patients in the weeks before and after surgery. The control group will receive usual care and will have access to a nonintervention (standard) website consisting of the digital information brochure about the surgical procedure being performed. Patients are asked to complete questionnaires at 5 moments during the first 6 months after surgery. The primary outcome measure is time to return to normal activities based on a patient-specific set of 8 activities selected from the Patient-Reported Outcomes Measurement Information System (PROMIS) physical functioning item bank version 1.2. Secondary outcomes include social participation, self-rated health, duration of return to work, physical activity, length of recovery, pain intensity, and patient satisfaction. In addition, an economic evaluation alongside this randomized controlled trial will be performed from the societal and health care perspective. All statistical analyses will be conducted according to the intention-to-treat principle., Results: The enrollment of patients started in September 2015. The follow-up period will be completed in February 2017. Data cleaning and analyses have not begun as of the time this article was submitted., Conclusions: We hypothesize that patients receiving the intervention program will resume their normal activities sooner than patients in the control group and costs will be lower., Clinicaltrial: Netherlands Trial Registry NTC4699; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4699 (Archived by WebCite at http://www.webcitation.org/6mcCBZmwy)., Competing Interests: EM, JH, EB, CB, and JA are the developers of the care program under study. JA and JH are setting up a spin-off company concerning the implementation of a mobile application concerning the IKHERSTEL intervention in the Netherlands., (©Eva van der Meij, Judith AF Huirne, Esther VA Bouwsma, Johanna M van Dongen, Caroline B Terwee, Peter M van de Ven, Chantal M den Bakker, Suzan van der Meij, W Marchien van Baal, Wouter KG Leclercq, Peggy MAJ Geomini, Esther CJ Consten, Steven E Schraffordt Koops, Paul JM van Kesteren, Hein BAC Stockmann, A Dorien ten Cate, Paul HP Davids, Petrus C Scholten, Baukje van den Heuvel, Frederieke G Schaafsma, Wilhelmus JHJ Meijerink, H Jaap Bonjer, Johannes R Anema. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 21.12.2016.)
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- 2016
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26. A modified Delphi method toward multidisciplinary consensus on functional convalescence recommendations after abdominal surgery.
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van Vliet DC, van der Meij E, Bouwsma EV, Vonk Noordegraaf A, van den Heuvel B, Meijerink WJ, van Baal WM, Huirne JA, and Anema JR
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- Adult, Delphi Technique, Female, Humans, Male, Middle Aged, Postoperative Period, Convalescence, Digestive System Surgical Procedures
- Abstract
Background: Evidence-based information on the resumption of daily activities following uncomplicated abdominal surgery is scarce and not yet standardized in medical guidelines. As a consequence, convalescence recommendations are generally not provided after surgery, leading to patients' insecurity, needlessly delayed recovery and prolonged sick leave. The aim of this study was to generate consensus-based multidisciplinary convalescence recommendations, including advice on return to work, applicable for both patients and physicians., Method: Using a modified Delphi method among a multidisciplinary panel of 13 experts consisting of surgeons, occupational physicians and general practitioners, detailed recommendations were developed for graded resumption of 34 activities after uncomplicated laparoscopic cholecystectomy, laparoscopic and open appendectomy, laparoscopic and open colectomy and laparoscopic and open inguinal hernia repair. A sample of occupational physicians, general practitioners and surgeons assessed the recommendations on feasibility in daily practice. The response of this group of care providers was discussed with the experts in the final Delphi questionnaire round., Results: Out of initially 56 activities, the expert panel selected 34 relevant activities for which convalescence recommendations were developed. After four Delphi rounds, consensus was reached for all of the 34 activities for all the surgical procedures. A sample of occupational physicians, general practitioners and surgeons regarded the recommendations as feasible in daily practice., Conclusion: Multidisciplinary convalescence recommendations regarding uncomplicated laparoscopic cholecystectomy, appendectomy (laparoscopic, open), colectomy (laparoscopic, open) and inguinal hernia repair (laparoscopic, open) were developed by a modified Delphi procedure. Further research is required to evaluate whether these recommendations are realistic and effective in daily practice., Competing Interests: Compliance with ethical standards Disclosures Daphne C.R. van Vliet (M.D.), Eva van der Meij (M.D.), Esther V.A. Bouwsma (M.D.), Antonie Vonk Noordegraaf (M.D., Ph.D.), Baukje van den Heuvel (M.D., Ph.D.), Wilhelmus J.H.J. Meijerink (M.D., Ph.D.), W. Marchien van Baal (M.D., Ph.D.), Judith A.F. Huirne (M.D., Ph.D.) and Johannes R. Anema (M.D., Ph.D.) have no conflicts of interest or financial ties to disclose.
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- 2016
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27. Performance of CADM1/MAL-methylation analysis for monitoring of women treated for high-grade CIN.
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Uijterwaal MH, van Zummeren M, Kocken M, Luttmer R, Berkhof J, Witte BI, van Baal WM, Graziosi GCM, Verheijen RHM, Helmerhorst TJM, van Dijken DKE, Spruijt JWM, van Kemenade FJ, Fransen-Daalmeijer N, Bekker-Lettink M, Heideman DAM, Snijders PJF, Steenbergen RDM, and Meijer CJLM
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- Adult, Cell Adhesion Molecule-1, Female, Humans, Middle Aged, Prospective Studies, Cell Adhesion Molecules genetics, DNA Methylation, Immunoglobulins genetics, Myelin and Lymphocyte-Associated Proteolipid Proteins genetics, Uterine Cervical Neoplasms genetics, Uterine Cervical Dysplasia genetics
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Introduction: Recent studies have shown that CADM1/MAL-methylation testing detects high-grade CIN lesions with a high short-term progression risk for cervical cancer. Women treated for CIN2/3 are at risk of post-treatment disease, representing either persistent (incompletely treated) or incident (early onset) lesions. Here, we evaluated CADM1/MAL-methylation analysis as potential tool for detecting recurrent high-grade CIN lesions (rCIN2/3)., Methods and Materials: A multicenter prospective clinical cohort study was conducted among 364 women treated for CIN2/3. Cervical scrapes were taken prior to treatment, and six and 12months post-treatment and tested for cytology, hrHPV (plus genotype) and CADM1/MAL-methylation. When at six months either of these tests was positive, a colposcopy-directed biopsy was obtained. At 12months, all women underwent an exit-colposcopy with biopsy. In case of rCIN2/3, re-treatment was done., Results: We found 28 rCIN2 (7.7%) and 14 rCIN3 (3.8%), resulting in a total recurrence rate of 11.5%. All 14 women with rCIN3 and 15/28 (54%) with rCIN2 showed hrHPV type-persistence. Of these, 9/14 (64%) rCIN3 and 8/15 (53%) rCIN2 were CADM1/MAL-methylation positive. All incident rCIN2, characterized by hrHPV genotype-switch, were CADM1/MAL-methylation negative. All three carcinomas found after re-treatment were CADM1/MAL-methylation positive. CADM1/MAL-methylation positivity at both baseline and follow-up significantly increased the risk of ≥rCIN3 (from 0.7% to 18.4%), and ≥rCIN2 (from 8.2% to 36.8%), compared to a consistently CADM1/MAL-methylation negative result (p-value: <0.001)., Conclusion: Post-treatment monitoring by CADM1/MAL-methylation analysis identifies women with an increased risk of rCIN2/3. Our results confirm previous data indicating that CADM1/MAL-methylation analysis provides a high reassurance against cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)
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- 2016
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28. FAM19A4 methylation analysis in self-samples compared with cervical scrapes for detecting cervical (pre)cancer in HPV-positive women.
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Luttmer R, De Strooper LM, Dijkstra MG, Berkhof J, Snijders PJ, Steenbergen RD, van Kemenade FJ, Rozendaal L, Helmerhorst TJ, Verheijen RH, Ter Harmsel WA, van Baal WM, Graziosi PG, Quint WG, Spruijt JW, van Dijken DK, Heideman DA, and Meijer CJ
- Subjects
- Biopsy, Female, Humans, Precancerous Conditions diagnosis, Precancerous Conditions pathology, Precancerous Conditions virology, Uterine Cervical Neoplasms diagnosis, Uterine Cervical Neoplasms pathology, Uterine Cervical Neoplasms virology, Alphapapillomavirus isolation & purification, Cytokines genetics, DNA Methylation, Precancerous Conditions genetics, Uterine Cervical Neoplasms genetics
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Background: High-risk human papillomavirus (hrHPV)-positive women require triage to identify those with cervical high-grade intraepithelial neoplasia and cancer (⩾CIN3 (cervical intraepithelial neoplasia grade 3)). FAM19A4 methylation analysis, which detects advanced CIN and cancer, is applicable to different sample types. However, studies comparing the performance of FAM19A4 methylation analysis in hrHPV-positive self-samples and paired physician-taken scrapes are lacking., Methods: We compared the performance of FAM19A4 methylation analysis (and/or HPV16/18 genotyping) in self-samples and paired physician-taken scrapes for ⩾CIN3 detection in hrHPV-positive women (n=450,18-66 years)., Results: Overall FAM19A4 methylation levels between sample types were significantly correlated, with strongest correlation in women with ⩾CIN3 (Spearman's ρ 0.697, P<0.001). The performance of FAM19A4 methylation analysis and/or HPV16/18 genotyping did not differ significantly between sample types. In women ⩾30 years, ⩾CIN3 sensitivity of FAM19A4 methylation analysis was 78.4% in self-samples and 88.2% in scrapes (ratio 0.89; CI: 0.75-1.05). In women <30 years, ⩾CIN3 sensitivities were 37.5% and 45.8%, respectively (ratio 0.82; CI: 0.55-1.21). In both groups, ⩾CIN3 specificity of FAM19A4 methylation analysis was significantly higher in self-samples compared with scrapes., Conclusions: FAM19A4 methylation analysis in hrHPV-positive self-samples had a slightly lower sensitivity and a higher specificity for ⩾CIN3 compared with paired physician-taken scrapes. With a similarly good clinical performance in both sample types, combined FAM19A4 methylation analysis and HPV16/18 genotyping provides a feasible triage strategy for hrHPV-positive women, with direct applicability on self-samples., Competing Interests: JB has played an advisory role for Merck and Roche, has been on the speakers bureau of Qiagen and has received a travel reimbursement from DDL Diagnostic Laboratory. PJFS has been on the speakers bureau of Roche, Qiagen, Abbott, Gen-Probe and Seegene. PJFS is consultant for Crucell Holland BV. TJMH, RHMV and WAH have been principal investigators of a GlaxoSmithKline sponsored study. WGVQ is a minority shareholder of Diassay BV and obtained grants from GlaxoSmithKline. DAMH has been on the speakers bureau of Hologic/Gen-Probe and serves occasionally on the scientific advisory boards of AMGEN and Pfizer. CJLMM has been on the sponsored speakers bureau of GlaxoSmithKline, Qiagen, Merck, Roche, Menarini and Segeene, and served on the scientific advisory board of GlaxoSmithKline, Qiagen, Merck and Roche. CJLMM has been consultant for Qiagen and Genticel and is a minority shareholder of Diassay BV. Formerly, CJLMM was a minority shareholder of Delphi Biosciences. CJLMM, PJFS, RDMS and DAMH have minority stake in Self-screen BV, a spin-off company of VU University Medical Center Amsterdam, which holds patents related to the present work. RL, LMADS, MGD, FJvK, LR, WMvB, GCMG, JWMS and DKEvD do not have any conflict of interest to declare.
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- 2016
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29. p16/Ki-67 dual-stained cytology for detecting cervical (pre)cancer in a HPV-positive gynecologic outpatient population.
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Luttmer R, Dijkstra MG, Snijders PJ, Berkhof J, van Kemenade FJ, Rozendaal L, Helmerhorst TJ, Verheijen RH, Ter Harmsel WA, van Baal WM, Graziosi PG, Quint WG, Spruijt JW, van Dijken DK, Heideman DA, and Meijer CJ
- Subjects
- Adolescent, Adult, Aged, Female, Genotype, Human Papillomavirus DNA Tests, Human papillomavirus 16 genetics, Human papillomavirus 18 genetics, Humans, Middle Aged, Netherlands, Papanicolaou Test, Papillomavirus Infections metabolism, Papillomavirus Infections pathology, Papillomavirus Infections virology, Precancerous Conditions metabolism, Precancerous Conditions pathology, Precancerous Conditions virology, Predictive Value of Tests, Prospective Studies, Reproducibility of Results, Triage, Vaginal Smears, Young Adult, Uterine Cervical Dysplasia chemistry, Uterine Cervical Dysplasia pathology, Uterine Cervical Dysplasia virology, Cyclin-Dependent Kinase Inhibitor p16 analysis, Immunohistochemistry, Ki-67 Antigen analysis, Outpatients, Papillomavirus Infections diagnosis, Precancerous Conditions diagnosis, Uterine Cervical Dysplasia diagnosis
- Abstract
Women who test positive for a high-risk type of the human papillomavirus (HPV) require triage testing to identify those women with cervical intraepithelial neoplasia grade 3 or cancer (≥CIN3). Although Pap cytology is considered an attractive triage test, its applicability is hampered by its subjective nature. This study prospectively compared the clinical performance of p16/Ki-67 dual-stained cytology to that of Pap cytology, with or without HPV16/18 genotyping, in high-risk HPV-positive women visiting gynecologic outpatient clinics (n=446 and age 18-66 years). From all women, cervical scrapes (for Pap cytology, HPV16/18 genotyping, and p16/Ki-67 dual-stained cytology) and colposcopy-directed biopsies were obtained. The sensitivity of p16/Ki-67 dual-stained cytology for ≥CIN3 (93.8%) did neither differ significantly from that of Pap cytology (87.7%; ratio 1.07 and 95% confidence interval (CI): 0.97-1.18) nor from that of Pap cytology combined with HPV16/18 genotyping (95.1%; ratio 0.99 and 95% CI: 0.91-1.07). However, the specificity of p16/Ki-67 dual-stained cytology for ≥CIN3 (51.2%) was significantly higher than that of Pap cytology (44.9%; ratio 1.14 and 95% CI: 1.01-1.29) and Pap cytology combined with HPV16/18 genotyping (25.8%; ratio 1.99 and 95% CI: 1.68-2.35). After exclusion of women who had been referred because of abnormal Pap cytology, the specificity of p16/Ki-67 dual-stained cytology for ≥CIN3 (56.7%) remained the same, whereas that of Pap cytology (60.3%) increased substantially, resulting in a similar specificity of both assays (ratio 0.94 and 95% CI: 0.83-1.07) in this sub-cohort. In summary, p16/Ki-67 dual-stained cytology has a good clinical performance and is an interesting objective microscopy-based triage tool for high-risk HPV-positive women.
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- 2016
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30. Comparing the performance of FAM19A4 methylation analysis, cytology and HPV16/18 genotyping for the detection of cervical (pre)cancer in high-risk HPV-positive women of a gynecologic outpatient population (COMETH study).
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Luttmer R, De Strooper LM, Berkhof J, Snijders PJ, Dijkstra MG, Uijterwaal MH, Steenbergen RD, van Kemenade FJ, Rozendaal L, Helmerhorst TJ, Verheijen RH, Ter Harmsel WA, Van Baal WM, Graziosi PG, Quint WG, Heideman DA, and Meijer CJ
- Subjects
- Adult, Aged, Cohort Studies, Female, Genotype, Humans, Middle Aged, Odds Ratio, Outpatients, Papillomavirus Infections complications, Risk Factors, Sensitivity and Specificity, Uterine Cervical Neoplasms genetics, Uterine Cervical Neoplasms virology, Vaginal Smears, Uterine Cervical Dysplasia genetics, Uterine Cervical Dysplasia virology, Biomarkers, Tumor genetics, Chemokines genetics, Cytokines genetics, DNA Methylation genetics, Human papillomavirus 16 genetics, Human papillomavirus 18 genetics, Uterine Cervical Neoplasms diagnosis, Uterine Cervical Dysplasia diagnosis
- Abstract
Recently, DNA methylation analysis of FAM19A4 in cervical scrapes has been shown to adequately detect high-grade cervical intraepithelial neoplasia and cervical cancer (≥ CIN3) in high-risk HPV (hrHPV)-positive women. Here, we compared the clinical performance of FAM19A4 methylation analysis to cytology and HPV16/18 genotyping, separately and in combination, for ≥ CIN3 detection in hrHPV-positive women participating in a prospective observational multi-center cohort study. The study population comprised hrHPV-positive women aged 18-66 years, visiting a gynecological outpatient clinic. From these women, cervical scrapes and colposcopy-directed biopsies (for histological confirmation) were obtained. Cervical scrapes were analyzed for FAM19A4 gene promoter methylation, cytology and HPV16/18 genotyping. Methylation analysis was performed by quantitative methylation-specific PCR (qMSP). Sensitivities and specificities for ≥ CIN3 were compared between tests. Stratified analyses were performed for variables that potentially influence marker performance. Of all 508 hrHPV-positive women, the sensitivities for ≥ CIN3 of cytology, FAM19A4 methylation analysis, and cytology combined with HPV16/18 genotyping were 85.6, 75.6 and 92.2%, respectively, with corresponding specificities of 49.8, 71.1 and 29.4%, respectively. Both sensitivity and specificity of FAM19A4 methylation analysis were associated with age (p ≤ 0.001 each). In women ≥ 30 years (n = 287), ≥ CIN3 sensitivity of FAM19A4 methylation analysis was 88.3% (95%CI: 80.2-96.5) which was noninferior to that of cytology [85.5% (95%CI: 76.0-94.0)], at a significantly higher specificity [62.1% (95%CI: 55.8-68.4) compared to 47.6% (95%CI: 41.1-54.1)]. In conclusion, among hrHPV-positive women from an outpatient population aged ≥ 30 years, methylation analysis of FAM19A4 is an attractive marker for the identification of women with ≥ CIN3., (© 2015 UICC.)
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- 2016
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31. A personalised eHealth programme reduces the duration until return to work after gynaecological surgery: results of a multicentre randomised trial.
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Vonk Noordegraaf A, Anema JR, van Mechelen W, Knol DL, van Baal WM, van Kesteren PJ, Brölmann HA, and Huirne JA
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- Adnexa Uteri surgery, Adolescent, Adult, Aged, Female, Humans, Hysterectomy adverse effects, Laparoscopy adverse effects, Middle Aged, Netherlands, Pain Measurement, Sick Leave statistics & numerical data, Time Factors, Treatment Outcome, Young Adult, Hysterectomy rehabilitation, Laparoscopy rehabilitation, Pain rehabilitation, Quality of Life, Return to Work statistics & numerical data, Telemedicine methods
- Abstract
Objective: To evaluate the effectiveness of an eHealth intervention on recovery and return to work, after gynaecological surgery., Design: Randomised multicentre trial that ran from March 2010 until September 2011., Setting: Secondary care in seven general and university hospitals in The Netherlands., Population: A cohort of 215 women (aged 18-65 years) who had a hysterectomy and/or laparoscopic adnexal surgery for a benign indication., Methods: The women were randomly assigned to the intervention group (n = 110) or the control group (n = 105). The intervention group received an eHealth programme that provided personalised tailor-made pre- and postoperative instructions on the resumption of daily activities, including work, and tools to improve self-empowerment and to identify recovery problems. The control group was provided with access to a control website., Main Outcome Measures: The primary outcome was the duration of sick leave until a full sustainable return to work. Secondary outcome measures were quality of life, general recovery, and pain intensity., Results: In intention-to-treat analysis the eHealth intervention was effective on time to return to work (hazard ratio 1.43; 95% confidence interval 1.003-2.040; P = 0.048). The median duration of sick leave until a full sustainable return to work was 39 days (interquartile range 20-67 days) in the intervention group and 48 days (interquartile range 21-69 days) in the control group. After 26 weeks pain intensity was lower (visual analogue scale, cumulative odds ratio 1.84; 95% confidence interval 1.04-3.25; P = 0.035) and quality of life was higher (Rand-36 health survey, between-group difference 30, 95% confidence interval 4-57; P = 0.024) in the intervention group, compared with the control group., Conclusions: The use of the eHealth intervention by women after gynaecological surgery results in a faster return to work, with a higher quality of life and less pain., (© 2014 Royal College of Obstetricians and Gynaecologists.)
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- 2014
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32. The cost effectiveness of a tailored, web-based care program to enhance postoperative recovery in gynecologic patients in comparison with usual care: protocol of a stepped wedge cluster randomized controlled trial.
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Bouwsma EV, Anema JR, Vonk Noordegraaf A, Knol DL, Bosmans JE, Schraffordt Koops SE, van Kesteren PJ, van Baal WM, Lips JP, Emanuel MH, Scholten PC, Mozes A, Adriaanse AH, Brölmann HA, and Huirne JA
- Abstract
Background: The length of recovery after benign gynecological surgery and return to work frequently exceeds the period that is recommended or expected by specialists. A prolonged recovery is associated with a poorer quality of life. In addition, costs due to prolonged sick leave following gynecological surgery cause a significant financial burden on society., Objective: The objective of our study was to present the protocol of a stepped wedge cluster randomized controlled trial to evaluate the cost effectiveness of a new care program for patients undergoing hysterectomy and/or adnexal surgery for benign disease, compared to the usual care., Methods: The care program under study, designed to improve convalescence and to prevent delayed return to work, targets two levels. At the hospital level, guidelines will be distributed among clinical staff in order to stimulate evidence-based patient education. At the patient level, additional perioperative guidance is provided by means of an eHealth intervention, equipping patients with tailored convalescence advice, and an occupational intervention is available for those patients at risk of prolonged sick leave. Due to the stepped wedge design of the trial, the care program will be sequentially rolled out among the 9 participating hospitals, from which the patients are recruited. Eligible for this study are employed women, 18-65 years of age, who are scheduled for hysterectomy and/or laparoscopic adnexal surgery. The primary outcome is full sustainable return to work. The secondary outcomes include general recovery, quality of life, self-efficacy, coping, and pain. The data will be collected by means of self-reported electronic questionnaires before surgery and at 2, 6, 12, 26, and 52 weeks after surgery. Sick leave and cost data are measured by monthly sick leave calendars, and cost diaries during the 12 month follow-up period. The economic evaluation will be performed from the societal perspective. All statistical analyses will be conducted according to the intention-to-treat principle., Results: The enrollment of the patients started October 2011. The follow-up period will be completed in August 2014. Data cleaning or analysis has not begun as of this article's submission., Conclusions: We hypothesize the care program to be effective by means of improving convalescence and reducing costs associated with productivity losses following gynecological surgery. The results of this study will enable health care policy makers to decide about future implementation of this care program on a broad scale., Trial Registration: Netherlands Trial Register: NTR2933; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2933 (Archived by WebCite at http://www.webcitation.org/6Q7exPG84).
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- 2014
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33. Brush-based self-sampling in combination with GP5+/6+-PCR-based hrHPV testing: high concordance with physician-taken cervical scrapes for HPV genotyping and detection of high-grade CIN.
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Dijkstra MG, Heideman DA, van Kemenade FJ, Hogewoning KJ, Hesselink AT, Verkuijten MC, van Baal WM, Boer GM, Snijders PJ, and Meijer CJ
- Subjects
- Adult, Aged, Female, Humans, Middle Aged, Papillomaviridae classification, Papillomaviridae genetics, Patient Acceptance of Health Care statistics & numerical data, Polymerase Chain Reaction methods, Papillomaviridae isolation & purification, Papillomavirus Infections diagnosis, Self-Examination methods, Specimen Handling methods, Uterine Cervical Dysplasia diagnosis
- Abstract
Background: Studies have shown that self-sampling for hrHPV testing (HPV self-sampling) is highly acceptable to women, increases screening participation rate, and may therefore further reduce cervical cancer incidence. However, it is important to clinically validate HPV self-sampling procedures for screening purposes., Objectives: Clinical validation of combined brush-based self-sampling with GP5+/6+-PCR EIA for primary cervical screening. In addition, HPV type-specific agreement between sample types and acceptability of brush-based self-sampling were evaluated., Study Design: 135 women referred for colposcopy took a self-sample at home prior to vaginal- and cervical sampling by a gynaecologist. All women were biopsied for histology. HPV testing was done by GP5+/6+-PCR EIA, with genotyping by reverse line blotting (RLB). Acceptability of sampling methods was measured with a questionnaire., Results: In this outpatient population, hrHPV test results showed good concordance between self-samples and physician-taken cervical scrapes (86%, k=0.70), with sensitivities and specificities for CIN2+ that did not differ significantly (93% and 51%, 91% and 51%, respectively (P=1.0)). The clinical sensitivity of brush-based self-sampling combined with GP5+/6+-PCR EIA hrHPV testing for detection of CIN2+ was non-inferior to that of hrHPV testing on physician-taken cervical samples (P=0.018). In addition, hrHPV genotyping results were highly concordant between sample types, with almost perfect agreement for HPV16 (k=0.81) and HPV18 (k=0.92). Finally, 91% of participants described brush-based self-sampling as easy-to-use., Conclusions: Brush-based self-sampling in combination with GP5+/6+-PCR EIA hrHPV testing is acceptable to women and valid for assessing the risk of CIN2+ in comparison to hrHPV testing on physician-taken scrapes. In addition, there was high concordance of HPV genotyping results. Therefore, this HPV self-sampling procedure may be considered for use in routine cervical screening., (Copyright © 2012. Published by Elsevier B.V.)
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- 2012
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34. HrHPV-testing in a university hospital gynecology outpatient clinic: recommendations for clinical practice.
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Louwers JA, Berkhof J, Zaal A, Kocken M, Rozendaal L, Heideman DA, van Baal WM, Snijders PJ, Verheijen RH, and Meijer CJ
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Ambulatory Care methods, Cervix Uteri pathology, Cohort Studies, Female, Follow-Up Studies, Gynecology methods, Gynecology standards, Hospitals, University, Humans, Middle Aged, Papillomavirus Infections pathology, Uterine Cervical Neoplasms pathology, Young Adult, Uterine Cervical Dysplasia pathology, Cervix Uteri virology, Papillomaviridae isolation & purification, Papillomavirus Infections virology, Uterine Cervical Neoplasms virology, Uterine Cervical Dysplasia virology
- Abstract
Objective: To study the effect of hrHPV-testing on the detection of CIN2/3+ in women referred to a gynecology outpatient clinic, and to assess a useful risk profile in relation to the referral reason to identify who should be tested for cervical pathology., Methods: This study was designed as an observational cohort study. In the first six months of 2007, we categorized the referral reason of 1149 consecutive women who visited our gynecology outpatient clinic and assessed the risk for CIN2/3+ as found by cytology or co-testing with a hrHPV-test and cytology., Results: Three different categories of referral reasons were identified; women with presumed cervix pathology, women with presumed endometrial pathology and women with other referral indications. The cumulative 18-month CIN2+ and CIN3+ risks were highest in the group with presumed cervical disease (adjusted risks 11.1% and 5.4% respectively) and lowest in the miscellaneous group with no suspicion of cervical and/or endometrial pathology (adjusted risks 4.1% and 1.8% respectively). HrHPV-testing detected significantly more CIN2/3+ lesions than cytology (relative detection rate: 1.42 (95%CI 1.05-1.92) and 1.38 (95%CI 0.95-2.05) respectively)., Conclusions: The high (>2%) cumulative 18-month CIN2/3+ risk in patients with presumed cervical and/or endometrial pathology warrants routine cervical testing. In these women a hrHPV-test should be added to cytology because this identifies a significant number of additional women with a substantial risk of CIN2/3+ lesions who would not be identified with cytology alone. Women referred for other reasons should not have cervical testing beforehand, because of their low risk of CIN2/3+., (Copyright © 2011 Elsevier Inc. All rights reserved.)
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- 2012
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35. Combined CADM1 and MAL promoter methylation analysis to detect (pre-)malignant cervical lesions in high-risk HPV-positive women.
- Author
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Overmeer RM, Louwers JA, Meijer CJ, van Kemenade FJ, Hesselink AT, Daalmeijer NF, Wilting SM, Heideman DA, Verheijen RH, Zaal A, van Baal WM, Berkhof J, Snijders PJ, and Steenbergen RD
- Subjects
- Adolescent, Adult, Aged, Cell Adhesion Molecule-1, Cross-Sectional Studies, Early Detection of Cancer, Female, Humans, Middle Aged, Neoplasm Grading, Papillomavirus Infections virology, Precancerous Conditions genetics, Precancerous Conditions virology, Young Adult, Uterine Cervical Dysplasia genetics, Uterine Cervical Dysplasia virology, Cell Adhesion Molecules genetics, DNA Methylation, Immunoglobulins genetics, Myelin and Lymphocyte-Associated Proteolipid Proteins genetics, Precancerous Conditions diagnosis, Promoter Regions, Genetic, Uterine Cervical Dysplasia diagnosis
- Abstract
Given the lower specificity for high-grade cervical lesions of high-risk human papillomavirus (hrHPV) testing compared to cytology, additional triage testing for hrHPV test-positive women is needed to detect high-grade cervical lesions. Here, we tested whether combined methylation analysis for cell adhesion molecule 1 (CADM1) and T-lymphocyte maturation associated protein (MAL), both functionally involved in cervical carcinogenesis, could serve as such a triage marker. Four quantitative methylation-specific PCRs (qMSP), two for CADM1 (regions M12 and M18) and MAL (regions M1 and M2) each, were applied to 261 cervical tissue specimens ranging from no neoplasia to carcinoma. When qMSPs were combined and positivity for at least one of the qMSPs in the combination was taken into account, the highest positivity rates for cervical intraepithelial neoplasia grade 3 (CIN3) lesions (97%) and squamous cell- and adeno-carcinomas (99%) were obtained by combining a single CADM1 marker with a single MAL marker. Subsequent qMSP analysis of 70 GP5+/6+-PCR hrHPV-positive scrapings revealed that a two-marker panel consisting of CADM1-M18 and MAL-M1 was most discriminative, detecting 90% of women with CIN3 (n = 30), whereas it showed a positive result in only 13.5% of women without cervical disease (n = 40). Finally, we applied hrHPV GP5+/6+-PCR testing followed by CADM1-M18/MAL-M1 methylation analysis to a cohort of 79 women visiting the outpatient colposcopy clinic. hrHPV testing revealed a sensitivity of 97% and a specificity of 33% for CIN3+. Additional CADM1-M18/MAL-M1 methylation analysis on the hrHPV-positive women increased the specificity to 78% with a sensitivity of 70%. In conclusion, the methylation marker panel CADM1-M18 and MAL-M1 may serve as an alternative molecular triage tool for hrHPV-positive women., (Copyright © 2011 UICC.)
- Published
- 2011
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36. From open radical hysterectomy to robot-assisted laparoscopic radical hysterectomy for early stage cervical cancer: aspects of a single institution learning curve.
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Schreuder HW, Zweemer RP, van Baal WM, van de Lande J, Dijkstra JC, and Verheijen RH
- Abstract
We analysed the introduction of the robot-assisted laparoscopic radical hysterectomy in patients with early-stage cervical cancer with respect to patient benefits and surgeon-related aspects of a surgical learning curve. A retrospective review of the first 14 robot-assisted laparoscopic radical hysterectomies and the last 14 open radical hysterectomies in a similar clinical setting with the same surgical team was conducted. Patients were candidates for a laparoscopic sentinel node procedure, pelvic lymph node dissection and open radical hysterectomy (RH) before August 2006 and were candidates for a laparoscopic sentinel node procedure, pelvic lymph node dissection and robot-assisted laparoscopic radical hysterectomy (RALRH) after August 2006. Overall, blood loss in the open cases was significantly more compared with the robot cases. Median hospital stay after RALRH was 5 days less than after RH. The median theatre time in the learning period for the robot procedure was reduced from 9 h to less that 4 h and compared well to the 3 h and 45 min for an open procedure. Three complications occurred in the open group and one in the robot group. RALRH is feasible and of benefit to the patient with early stage cervical cancer by a reduction of blood loss and reduced hospital stay. Introduction of this new technique requires a learning curve of less than 15 cases that will reduce the operating time to a level comparable to open surgery.
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- 2010
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37. Methylation profiles of endometrioid and serous endometrial cancers.
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Seeber LM, Zweemer RP, Marchionni L, Massuger LF, Smit VT, van Baal WM, Verheijen RH, and van Diest PJ
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Endometrioid metabolism, Carcinoma, Endometrioid pathology, Cystadenocarcinoma, Serous metabolism, Cystadenocarcinoma, Serous pathology, DNA, Neoplasm genetics, DNA, Neoplasm metabolism, Endometrial Neoplasms metabolism, Endometrial Neoplasms pathology, Female, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Middle Aged, Proportional Hazards Models, Retrospective Studies, Site-Specific DNA-Methyltransferase (Adenine-Specific) metabolism, Carcinoma, Endometrioid genetics, Cystadenocarcinoma, Serous genetics, DNA Methylation, Endometrial Neoplasms genetics, Genes, Tumor Suppressor
- Abstract
Promoter methylation is a gene- and cancer type-specific epigenetic event that plays an important role in tumour development. As endometrioid (endometrioid endometrial carcinoma, EEC) and serous endometrial cancers (uterine papillary serous carcinoma, UPSC) exhibit different clinical, histological and molecular genetic characteristics, we hypothesized that these differences may be reflected in epigenetic phenomena as well. Identification of a panel of methylation biomarkers could be helpful in a correct histological classification of these two subtypes, which solely on the basis of morphology is not always easy. Methylation-specific multiplex ligation-dependent probe amplification was used to assess the extent of promoter methylation of different tumour suppressor genes in EEC and UPSC. Methylation results were correlated with histology and survival. The median cumulative methylation index of all genes was significantly higher in EEC (124) than in UPSC (93) (P<0.001). Promoter methylation of CDH13 and MLH1 was more frequently present in EEC, while CDKN2B and TP73 were more frequently methylated in UPSC. Almost 90% of EEC and 70% of UPSC could be predicted by CDH13 and TP73. In EEC, methylation of MLH1 was associated with a shorter disease-free survival (DFS; P<0.0001) and overall survival (OS; P=0.005). In a multivariate model, MLH1 methylation emerged as an additional prognostic factor to stage for DFS (P=0.002). In conclusion, promoter methylation is more common in EEC than UPSC. A panel of methylation biomarkers could be useful to distinguish between the two histological subtypes of endometrial cancer. Furthermore, methylation of MLH1 may have prognostic value in EEC.
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- 2010
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38. SCC-Ag, lymph node metastases and sentinel node procedure in early stage squamous cell cervical cancer.
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van de Lande J, Davelaar EM, von Mensdorff-Pouilly S, Water TJ, Berkhof J, van Baal WM, Kenemans P, and Verheijen RH
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- Adult, Aged, Aged, 80 and over, Carcinoma, Squamous Cell surgery, Female, Humans, Lymph Node Excision, Lymph Nodes surgery, Lymphatic Metastasis, Middle Aged, Neoplasm Staging, Prognosis, Proportional Hazards Models, Uterine Cervical Neoplasms surgery, Young Adult, Antigens, Neoplasm blood, Carcinoma, Squamous Cell blood, Carcinoma, Squamous Cell pathology, Lymph Nodes pathology, Sentinel Lymph Node Biopsy methods, Serpins blood, Uterine Cervical Neoplasms blood, Uterine Cervical Neoplasms pathology
- Abstract
Objectives: We analyzed pretreatment SCC-Ag levels, lymph node (LN) status and disease outcome in early stage squamous cell (SCC) cervical cancer., Methods: Serum SCC-Ag was measured before primary treatment in 91 patients (FIGO stage IB1 72, IB2 10, and IIA 9). Of these, 58 underwent laparoscopic sentinel lymph node (SLN) procedure followed by pelvic lymphadenectomy., Results: No false negative SLN were observed. SCC-Ag levels were higher in patients with positive LN compared to patients with negative LN (p=0.010), but no difference was found in the SLN patients (p=0.344). The accuracy to predict LN metastases of SCC-Ag at ROC established cutoff of 1.65 ng/mL and 5.5 ng/mL was 76% and 78%, respectively, in stage IB1, and 53% and 79%, respectively, in stages IB2+ IIA. Whereas no deaths were observed in patients with negative LN and negative SCC-Ag levels (at previously established cutoff of 1.1 ng/mL), overall survival (OS) for patients with negative LN but elevated SCC-Ag was similar to that of patients with positive LN, irrespective of their marker levels (Kaplan-Meier analysis of all patients and in stage IB1, p=0.002 and p=0.026, respectively)., Conclusions: SCC-Ag (>1.65 ng/mL) can predict LN metastases more accurately in stage IB1 than in stage IB2+ IIA. Since SCC-Ag levels above 1.1 ng/mL are already associated with a poor prognosis, the marker seems to identify a subgroup of LN negative patients with occult disease that may benefit from full lymphadenectomy following a SLN procedure.
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- 2009
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39. Different effects of low-dose transdermal and oral oestrogen therapy on procarboxy-peptidase U, an inhibitor of fibrinolysis, in healthy postmenopausal women: a randomised, placebo-controlled study.
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Post MS, Leurs JR, van der Mooren MJ, van Baal WM, Hendriks DF, Stehouwer CD, and Kenemans P
- Subjects
- Drug Administration Routes, Estradiol administration & dosage, Estradiol pharmacology, Female, Fibrinolysis, Humans, Middle Aged, Postmenopause, Carboxypeptidase B2 blood, Estrogen Replacement Therapy adverse effects
- Published
- 2005
40. Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis: a randomized, placebo-controlled study in postmenopausal women.
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Post MS, Christella M, Thomassen LG, van der Mooren MJ, van Baal WM, Rosing J, Kenemans P, and Stehouwer CD
- Subjects
- Administration, Cutaneous, Administration, Oral, Aged, Biomarkers, C-Reactive Protein analysis, Double-Blind Method, Estradiol adverse effects, Estradiol pharmacology, Female, Humans, Middle Aged, Norpregnenes administration & dosage, Norpregnenes adverse effects, Protein S analysis, Prothrombin analysis, Risk Factors, Venous Thrombosis chemically induced, Activated Protein C Resistance chemically induced, Estradiol administration & dosage, Estrogen Replacement Therapy, Hemostasis drug effects, Norpregnenes pharmacology, Postmenopause blood, Protein C analysis, Venous Thrombosis blood
- Abstract
Objective: The purpose of this study was to investigate whether the effect of transdermal estrogen therapy in postmenopausal women differs from that of oral therapy with regard to resistance to activated protein C (APC), an important risk factor for venous thrombosis, and levels of related proteins, such as protein S, protein C, and prothrombin., Methods and Results: In a randomized, double-blind, placebo-controlled study, 152 healthy hysterectomized postmenopausal women received daily either placebo (n=49), transdermal 17beta-estradiol (E2) 50 microg (tE2 group, n=33), oral E2 1 mg (oE2 group, n=37), or oral E2 1 mg combined with gestodene 25 microg (oE2+G group, n=33) for 13 28-day treatment cycles, followed by 4 cycles of placebo for each group. Plasma samples were collected at baseline and in cycles 4, 13, and 17. In cycle 13, significant increases versus baseline and placebo were found in normalized APC sensitivity ratios (nAPCsr) in all treated groups (tE2, +26.9%; oE2, +102.7%; oE2+G, +69.9%). Increases in nAPCsr were significantly higher in the oral treatment groups than in the tE2 group. In addition, compared with baseline and placebo, after 13 cycles, decreases were observed in total protein S (tE2, -4.1%; oE2, -7.9%; oE2+G, -5.8%), free protein S (tE2, -7.1%; oE2, -8.4%; oE2+G, -5.2%), and protein C in the oE2+G group (-6.4%), but these changes did not explain the increase in nAPCsr. Changes in prothrombin were small and also did not affect the nAPCsr., Conclusions: Increases were observed in resistance to APC, which were more pronounced in the oral treatment groups than in the transdermal group. The increase in resistance to APC was not explained by changes in protein S, protein C, or prothrombin and may contribute to the increased incidence of venous thrombosis in users of hormone replacement therapy.
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- 2003
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41. Increased resistance to activated protein C after short-term oral hormone replacement therapy in healthy post-menopausal women.
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Post MS, Rosing J, Van Der Mooren MJ, Zweegman S, Van Baal WM, Kenemans P, and Stehouwer CD
- Subjects
- Activated Protein C Resistance blood, Analysis of Variance, Double-Blind Method, Drug Combinations, Dydrogesterone adverse effects, Factor VIII metabolism, Factor XI metabolism, Female, Humans, Middle Aged, Promegestone adverse effects, Prospective Studies, Activated Protein C Resistance chemically induced, Estradiol adverse effects, Estrogen Replacement Therapy adverse effects, Postmenopause blood, Promegestone analogs & derivatives
- Abstract
As hormone replacement therapy is associated with an early excess risk of venous thrombosis, we investigated the effect of different oral hormone replacement therapies on resistance to activated protein C, and on levels of factor VIII antigen (FVIII:Ag) and factor XI antigen (FXI:Ag). In a prospective, randomized, placebo-controlled 12-week study, 60 healthy post-menopausal women daily received either placebo (n = 16) or 2 mg of micronized 17beta-oestradiol, either alone (E2, n = 16) or sequentially combined with dydrogesterone 10 mg (E2 + D, n = 14) or trimegestone 0.5 mg (E2 + T, n = 14). Medication was given orally. Normalized activated protein C sensitivity ratios (nAPCsr) were determined by quantifying the effect of activated protein C on the endogenous thrombin potential. FVIII:Ag and FXI:Ag were determined by enzyme-linked immunosorbent assay. Compared with baseline and placebo, the nAPCsr increased (92% to 142%; all P < 0.001) in all active treatment groups after both 4 and 12 weeks. Compared with placebo, hormone replacement therapy was not associated with significant changes in FVIII:Ag. After 4 and 12 weeks, FXI:Ag levels were significantly decreased in the E2 group (mean percentage changes from baseline versus placebo: -15.0%, P = 0.001 at 4 weeks and -16.6%, P = 0.003 at 12 weeks) and in the E2 + D group (-10.4%, P = 0.02 and -10.4%, P = 0.02). In conclusion, all hormone replacement regimens were associated with a large increase in resistance to activated protein C. In contrast, hormone replacement therapy had no effect on FVIII:Ag. Oral E2 and E2 + D had a small, favourable effect on FXI:Ag.
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- 2002
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42. Effects of transdermal and oral oestrogen replacement therapy on C-reactive protein levels in postmenopausal women: a randomised, placebo-controlled trial.
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Post MS, van der Mooren MJ, Stehouwer CD, van Baal WM, Mijatovic V, Schalkwijk CG, and Kenemans P
- Subjects
- Administration, Cutaneous, Administration, Oral, Arteriosclerosis blood, Biomarkers blood, C-Reactive Protein analysis, Drug Therapy, Combination, Estradiol administration & dosage, Estradiol adverse effects, Estrogen Replacement Therapy methods, Female, Humans, Middle Aged, Norpregnenes administration & dosage, Placebos, Postmenopause blood, C-Reactive Protein drug effects, Estrogen Replacement Therapy adverse effects
- Abstract
To investigate the effect of postmenopausal oral and transdermal hormone therapy on plasma levels of C-reactive protein (CRP), we performed a randomised, double-blind, double-dummy, placebo-controlled, 15-month study. One hundred and fifty-two healthy hysterectomised postmenopausal women received daily either placebo (n = 49), or transdermal 17beta-oestradiol (E(2)) 50 micro g (tE(2) group, n = 33), or oral E(2) 1 mg (oE(2) group, n = 37), or oral E(2) 1 mg combined with gestodene 25 micro g (oE(2) + G group, n = 33) for thirteen 28-day treatment cycles, followed by four cycles placebo for each group. Data were collected at baseline and in cycles 4, 13 and 17. In cycle 13, CRP was significantly increased in the oE(2) group compared to placebo (P = 0.004). The median percentage change from baseline versus placebo was +75% (P <0.001). In cycle 17, significantly lower values were observed in the oE(2) group compared to cycle 13 and to the placebo group (-49%, P <0.001). There were no significant changes versus placebo in the other groups. In conclusion, oral E(2) significantly increased CRP levels. This change was larger than the increase found during oral E(2) + G. Transdermal E(2) did not affect CRP levels.
- Published
- 2002
43. Effects of hormone replacement therapy on blood platelets.
- Author
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Thijs A, van Baal WM, van der Mooren MJ, Kenemans P, Dräger AM, Huijgens PC, and Stehouwer CD
- Subjects
- Antigens, CD blood, Biomarkers blood, Dydrogesterone therapeutic use, Female, Flow Cytometry, Humans, Middle Aged, P-Selectin blood, Platelet Membrane Glycoproteins, Progesterone Congeners therapeutic use, Promegestone therapeutic use, Prospective Studies, Tetraspanin 30, Arteriosclerosis chemically induced, Estradiol therapeutic use, Estrogen Replacement Therapy adverse effects, Platelet Activation drug effects, Promegestone analogs & derivatives
- Abstract
Background: Hormone replacement therapy (HRT) increases the risk of cardiovascular morbidity in postmenopausal women under certain circumstances. Part of this effect may be the result of the influence of HRT on blood platelets. We studied the effect of short-term oral hormone replacement therapy (unopposed oestradiol or sequentially combined oestradiol and trimegestone or dydrogesterone) on platelet activation parameters in healthy postmenopausal women., Design: We designed a prospective, randomised, placebo-controlled 12-week study. Sixty healthy, normotensive, nonhysterectomised, postmenopausal women received daily micronised oestradiol (E2) 2 mg (n = 16), or 2 mg E2 daily sequentially combined with either trimegestone 0.5 mg daily (n = 14) or dydrogesterone 10 mg daily (n = 14), or placebo (n = 16). Data on platelet activation were collected at baseline and after 12 weeks of treatment using flow cytometry., Results: Twelve weeks of treatment with combined HRT was associated with an increase in platelet activation parameters P-selectin and glycoprotein 53 (by 17% and 14%, respectively, P = 0.04 vs. the placebo group for both comparisons), suggesting alpha granule and lysosome degranulation. E2 replacement therapy was associated with an increase in P-selectin labelling by 22% (P = 0.04 vs. the placebo group)., Conclusion: Short-term treatment with oestradiol or combined HRT increases the amount of circulating activated platelets as measured by flow cytometry. This could be a mechanism by which short-term HRT might increase the risk of thrombosis.
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- 2002
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44. Oral oestradiol/trimegestone replacement reduces procarboxypeptidase U (TAFI): a randomized, placebo- controlled, 12-week study in early postmenopausal women.
- Author
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Post MS, Hendriks DF, Van Der Mooren MJ, Van Baal WM, Leurs JR, Emeis JJ, Kenemans P, and Stehouwer CD
- Subjects
- Female, Humans, Middle Aged, Postmenopause physiology, Prospective Studies, Carboxypeptidase B2 blood, Estradiol, Estrogen Replacement Therapy, Promegestone analogs & derivatives
- Abstract
Objective: To investigate the effects of short-term postmenopausal oral hormone administration on plasma levels of procarboxypeptidase U (proCPU, thrombin-activatable fibrinolysis inhibitor, EC 3.4.17.20), an inhibitor of fibrinolysis, in healthy early postmenopausal women., Design: A prospective, randomized, placebo-controlled study., Setting: Outpatient clinic of the Department of Obstetrics and Gynaecology., Subjects: Seventy-seven healthy early postmenopausal women were screened of whom 65 were randomized. Analyses were based on 60 participants., Interventions: The women received oral micronized oestradiol 2 mg either alone (E2 group, n=16), or sequentially combined with dydrogesterone 10 mg (E2 + D group, n=14) or trimegestone 0.5 mg (E2 + T, n=14), or placebo (n=16) for 12 weeks., Main Outcome Measure: ProCPU concentrations at baseline, and at 4 and 12 weeks of treatment., Results: Four weeks of E2 + T was associated with a significant decrease in the fasting proCPU concentration, which was sustained after 12 weeks [t=0: 636 +/- 57 U L(-1) (mean +/- SD); t=4: 583 +/- 63UL-1; t=12: 589 +/- 48 U L(-1); ANCOVA versus placebo: P=0.011]. The percentage change from baseline versus placebo in this group was -8.4% [95% confidence interval (CI) -15.7 to -1.1] after 4 weeks and -5.9% (95% CI -11.7 to -0.1) after 12 weeks. There were no significant changes versus placebo in the E2 group nor in the E2 + D group., Conclusion: Short-term treatment with E2 + T, but not E2 alone or E2 + D, lowers proCPU concentration. These findings add to accumulating evidence suggesting that different progestagens added to oestrogen replacement may differentially affect the risk of arterial and venous disease.
- Published
- 2002
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45. A 2-year, randomized, comparative, placebo-controlled study on the effects of raloxifene on lipoprotein(a) and homocysteine.
- Author
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Smolders RG, Vogelvang TE, Mijatovic V, van Baal WM, Neele SJ, Netelenbos JC, Kenemans P, and van der Mooren MJ
- Subjects
- Cardiovascular Diseases blood, Double-Blind Method, Estrogens, Conjugated (USP) administration & dosage, Female, Humans, Medroxyprogesterone Acetate administration & dosage, Middle Aged, Prospective Studies, Raloxifene Hydrochloride administration & dosage, Selective Estrogen Receptor Modulators administration & dosage, Cardiovascular Diseases prevention & control, Homocysteine blood, Hormone Replacement Therapy, Lipoprotein(a) blood, Raloxifene Hydrochloride therapeutic use, Selective Estrogen Receptor Modulators therapeutic use
- Abstract
Objectives: Lipoprotein(a) (Lp(a)) and homocysteine (Hcy) are independent cardiovascular risk factors, which have been shown to be lowered by hormone replacement therapy (HRT). In this 2-year study, the long-term effects of raloxifene (Rlx) in two doses, on Lp(a) and Hcy, were studied and compared with the effects of continuously combined hormone replacement therapy (ccHRT)., Methods: In a prospective, randomized, double-blind, placebo-controlled 2-year study, 95 healthy, non-hysterectomized, early postmenopausal women, received daily either oral Rlx 60 mg (N=24) or 150 mg (N=23), ccHRT (conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg; N=24) or placebo (N=24). Fasting serum Lp(a) and plasma Hcy concentrations were measured at baseline and at 6, 12 and 24 months., Results: The mean individual changes compared to baseline after 24 months were for Lp(a): Rlx 60: - 5%, Rlx 150: -7%, ccHRT: -34%, placebo: +1% and for Hcy: Rlx 60: -3%, Rlx 150: -4%, ccHRT: -4%, placebo: +6%. ANCOVA was significant for Lp(a) under ccHRT versus placebo (P=0.001) and for Lp(a) under ccHRT versus each of the two Rlx groups (P<0.05)., Conclusions: Long-term treatment with Rlx was not as effective as ccHRT in lowering Lp(a). Although not significant and without an obvious dose-related response, the Hcy values showed the same trend for each treatment arm, which is in line with data reported earlier.
- Published
- 2002
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46. The mechanisms of thrombotic risk induced by hormone replacement therapy.
- Author
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Cano A and Van Baal WM
- Subjects
- Aged, Arteriosclerosis physiopathology, Blood Platelets, Coronary Disease physiopathology, Endothelium, Vascular physiopathology, Estrogens pharmacology, Female, Hemostasis drug effects, Hemostasis physiology, Humans, Male, Middle Aged, Phenotype, Postmenopause drug effects, Risk Factors, Venous Thrombosis blood, Venous Thrombosis epidemiology, Venous Thrombosis genetics, Coronary Disease chemically induced, Coronary Disease prevention & control, Estrogen Replacement Therapy adverse effects, Venous Thrombosis chemically induced
- Abstract
Objectives: To review the available information on the action of hormones on the mechanisms involved in thrombotic risk., Results and Conclusions: Thrombosis plays a crucial role in the genesis and progression of both coronary heart disease (CHD) and venous thromboembolic disease (VTED), the two main forms of cardiovascular disease. Two main determinants of the thromboembolic phenotype, hypercoagulable state and altered endothelium, accumulate much of the work performed on the influence of hormones on thrombosis. Information has accumulated mainly for oestrogens, but increasing evidences support a role for progestogens. The sensitivity of each of the three components of the hemostatic balance, the coagulation cascade, the anticoagulant system and fibrinolysis, to oestrogens has been widely examined in the literature. Functional tests suggest that HRT is accompanied by a procoagulant state. Much of the work has concentrated on changes induced on reputable indicators of risk for either CHD or VTED. Distinct indicators of increased coagulability, such as resistance to activated C protein, antithrombin or tissue factor pathway inhibitor have been selected for VTED, whereas factor VII, fibrinogen, and defective fibrinolysis, for CHD. Different states of genetic susceptibility have been involved in both forms of the disease. The status of health of endothelium, defines another scenario for attention in CHD. A long-term anti-atherogenic action of oestrogens, which may be associated with short-term risk in cases of atherosclerosis-induced endothelial dysfunction, may most adequately explain much of the clinical observation. In both CHD and VTED, the procoagulant changes initiate soon after HRT administration.
- Published
- 2001
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47. Raloxifene reduces impedance to flow within the uterine artery in early postmenopausal women: a 2-year randomized, placebo-controlled, comparative study.
- Author
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Post MS, van der Mooren MJ, van Baal WM, Neele SJ, Netelenbos JC, and Kenemans P
- Subjects
- Arteries diagnostic imaging, Arteries drug effects, Dose-Response Relationship, Drug, Double-Blind Method, Estrogen Replacement Therapy, Female, Humans, Middle Aged, Placebos, Raloxifene Hydrochloride therapeutic use, Regional Blood Flow drug effects, Ultrasonography, Doppler, Color, Arteries physiology, Postmenopause, Raloxifene Hydrochloride administration & dosage, Selective Estrogen Receptor Modulators therapeutic use, Uterus blood supply
- Abstract
Objective: We sought to investigate the long-term effect of raloxifene and continuous combined hormone replacement therapy (ccHRT) on impedance to flow within the uterine artery in postmenopausal women., Study Design: A prospective, randomized, double-blind, placebo-controlled 2-year study was performed in 95 postmenopausal women. They received either 60 mg of raloxifene daily (raloxifene 60 group), 150 mg of raloxifene daily (raloxifene 150 group), ccHRT, or placebo. At baseline and thereafter every 6 months, color Doppler ultrasonography was used to measure the pulsatility index (PI) of the uterine artery., Results: After 24 months of treatment, compared with placebo, significant decreases were found in the PI in the raloxifene 150 group (P = .021) and in the ccHRT group (P = .007). In the raloxifene 150 group compared with the placebo group, after 6 and 24 months, decreases were observed in median PI of -5% and -15%, respectively, and in the ccHRT group decreases of -2% and -19%, respectively, were found., Conclusion: Long-term use of 150 mg of raloxifene daily or ccHRT reduces impedance to flow within the uterine artery. This indicates that high-dose raloxifene may exert cardiovascular protection.
- Published
- 2001
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48. Effects of 15 months of 17 beta-estradiol and dydrogesterone on systolic cardiac function according to quantitative and Doppler echocardiography in healthy postmenopausal women.
- Author
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Kessel H, Kamp O, Kenemans P, Mijatovic V, van Baal WM, Visser CA, and van der Mooren MJ
- Subjects
- Double-Blind Method, Drug Administration Schedule, Dydrogesterone administration & dosage, Echocardiography, Doppler drug effects, Estradiol administration & dosage, Female, Heart physiology, Humans, Middle Aged, Progesterone Congeners administration & dosage, Prospective Studies, Statistics, Nonparametric, Stroke Volume drug effects, Systole drug effects, Systole physiology, Dydrogesterone pharmacology, Estradiol pharmacology, Estrogen Replacement Therapy, Heart drug effects, Progesterone Congeners pharmacology
- Abstract
Objective: Our goal was to investigate the short-term and intermediate effects of low-dose hormone replacement therapy on echocardiographic parameters of cardiac function in healthy postmenopausal women., Study Design: In a prospective, controlled study 30 healthy postmenopausal women (mean age, 52 +/- 3 years) were randomly assigned to 2 groups. Women in the hormone replacement therapy group (n = 15) received 1 mg micronized 17 beta-estradiol daily sequentially combined with 5 or 10 mg dydrogesterone for 14 days of each 28-day cycle during 12 months and thereafter 2 mg 17 beta-estradiol combined with 10 mg dydrogesterone for a period of 3 months. The control group (n = 15) received no treatment. M-mode, quantitative 2-dimensional, and Doppler echocardiographic measurements were performed at baseline and within the 17 beta-estradiol phase at 3, 12, and 15 months., Results: After 12 months significant differences in change between the 2 groups were found for left ventricular end-diastolic and left ventricular end-systolic diameters, left ventricular mass index, and stroke volume index. These differences were caused by changes in the control group rather than in the hormone replacement therapy group, in which no significant within-group changes were found. All other parameters measured showed no effect., Conclusion: Within 15 months of 17 beta-estradiol and dydrogesterone treatment no clinically relevant differences were found in the M-mode, quantitative 2-dimensional, and Doppler echocardiographic parameters measured in this study. It is suggested that 15 months of treatment probably is too short a period for detection of direct effects on the heart itself.
- Published
- 2001
- Full Text
- View/download PDF
49. Cardiovascular disease risk and hormone replacement therapy (HRT): a review based on randomised, controlled studies in postmenopausal women.
- Author
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van Baal WM, Kooistra T, and Stehouwer CD
- Subjects
- Cardiovascular Diseases physiopathology, Female, Humans, Middle Aged, Randomized Controlled Trials as Topic, Risk Factors, Cardiovascular Diseases epidemiology, Estrogen Replacement Therapy
- Abstract
Epidemiological data suggest that the use of oestrogen replacement therapy (ERT) and combined oestrogen/progestagen replacement therapy (HRT) in healthy postmenopausal women is associated with a decreased risk of cardiovascular events. In sharp contrast, the HERS study, a secondary prevention trial in postmenopausal women with established coronary heart disease, did not show a favourable effect, with a trend towards an increased risk of cardiovascular disease in the first year of treatment. This paper provides an overview of randomised, controlled trials (RCTs) in postmenopausal women published in the literature and discusses possible explanations for the contrast between data from the epidemiological studies and the results of the HERS study. ERT and HRT are associated with: 1) an improved lipid profile; and 2) a decrease in homocysteine and endothelin levels. Data on factor VII and fibrinogen were not consistent. There were insufficient data on the effects on blood pressure, glucose metabolism, vasomotor regulation, arterial stiffness, thrombomodulin, adhesion molecules, and clotting and fibrinolysis, as well as on the effects of route of administration and the role of progestagens. Finally, endothelium-dependent vasodilatation appears to increase with ERT, but the effects of HRT are less clear This paucity of controlled data indicates that, although ERT and HRT improve surrogate measures of risk of atherothrombosis, adverse effects of ERT and HRT on biological mechanisms related to risk of atherothrombosis can by no means be excluded.
- Published
- 2000
- Full Text
- View/download PDF
50. Impaired procoagulant-anticoagulant balance during hormone replacement therapy? A randomised, placebo-controlled 12-week study.
- Author
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van Baal WM, Emeis JJ, van der Mooren MJ, Kessel H, Kenemans P, and Stehouwer CD
- Subjects
- Double-Blind Method, Estradiol administration & dosage, Estradiol adverse effects, Female, Humans, Middle Aged, Postmenopause, Progestins administration & dosage, Progestins adverse effects, Blood Coagulation drug effects, Hormone Replacement Therapy adverse effects
- Abstract
Unlabelled: In this randomised, placebo-controlled 12-week study, sixty healthy postmenopausal women received either placebo (N = 16) or daily 2 mg micronised oestradiol, either unopposed (N = 16, E2 group) or combined with a progestagen for 14 days of each cycle (N = 28, E2+P group)., Results: As compared to placebo, plasma levels of AT III were reduced only in the E2 group (approximately 28%), plasma levels of protein C decreased only in the E2+P group (approximately 4%) and plasma levels of protein S decreased in both the E2 and E2+P group (approximately 21%). In both the E2 and E2+P groups, the plasma levels of factor VII (antigen and activity) showed a borderline significant increase (approximately 10%), whereas no significant change was observed in active factor VII. Plasma levels of tissue-type plasminogen activator (approximately 22%), urokinase plasminogen activator (approximately 25%) and plasminogen activator inhibitor type-1 (approximately 43%) decreased in the E2 and E2+P groups, whereas those of plasminogen increased (approximately 12%). Treatment was associated with an increase in levels of prothrombin fragment 1+2 (approximately 31%), but levels of thrombin-antithrombin III complexes, and of plasmin-alpha2-antiplasmin complexes and total fibrin(ogen) degradation products did not change significantly., Conclusion: Short-term E2 and E2+P treatment is associated with a shift in the procoagulant-anticoagulant balance towards a procoagulant state. A substantial proportion of women do not have a net increase in fibrinolytic activity. These data may be relevant in explaining the increased risk of venous thromboembolism associated with ERT and HRT, and possibly also in explaining the negative results of the Heart and Estrogen/progestin Replacement Study.
- Published
- 2000
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