Publications by authors named "Ruud L M Bekkers"

76 Publications

A cost-effectiveness analysis of three approaches for lymph node assessment in patients with low- and intermediate-risk endometrial cancer.

Gynecol Oncol 2021 Feb 10. Epub 2021 Feb 10.

Radboud University Medical Center, Department of Obstetrics and Gynecology, Nijmegen, the Netherlands.

Objective: To assess the cost-effectiveness of sentinel lymph node mapping compared to risk factor assessment and routine full lymph node dissection for the assessment of lymph nodes in patients with low- and intermediate-risk endometrioid endometrial cancer.

Methods: A decision-analytic model was designed to compare three lymph node assessment strategies in terms of costs and effects: 1) sentinel lymph node mapping; 2) post-operative risk factor assessment (adjuvant therapy based on clinical and histological risk factors); 3) full lymph node dissection. Input data were derived from systematic literature searches and expert opinion. QALYs were used as measure of effectiveness. The model was built from a healthcare perspective and the impact of uncertainty was assessed with sensitivity analyses.

Results: Base-case analysis showed that sentinel lymph node mapping was the most effective strategy for lymph node assessment in patients with low- and intermediate-risk endometrial cancer. Compared to risk factor assessment it was more costly, but the incremental cost effectiveness ratio stayed below a willingness-to-pay threshold of €20,000 with a maximum of €9637/QALY. Sentinel lymph node mapping was dominant compared to lymph node dissection since it was more effective and less costly. Sensitivity analyses showed that the outcome of the model was robust to changes in input values. With a willingness-to-pay threshold of €20,000 sentinel lymph node mapping remained cost-effective in at least 74.3% of the iterations.

Conclusion: Sentinel lymph node mapping is the most cost-effective strategy to guide the need for adjuvant therapy in patients with low and intermediate risk endometrioid endometrial cancer.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.035DOI Listing
February 2021

Salvage surgery for patients with residual disease after chemoradiation therapy for locally advanced cervical cancer: A systematic review on indication, complications, and survival.

Acta Obstet Gynecol Scand 2021 Jan 20. Epub 2021 Jan 20.

Department of Obstetrics and Gynecology, Catherina Cancer Institute, Catharina Hospital, Eindhoven, the Netherlands.

Introduction: Standard treatment for locally advanced cervical cancer is chemoradiation therapy. Treatment with chemoradiation therapy harbors a risk of local residual disease, which can be curatively treated with salvage surgery, but the risk of complications following surgical procedures in radiated tissue is not negligible. The presence of residual disease can be radiologically and/or histologically diagnosed. The objective of this study is to describe studies that report on salvage surgery for patients with locally advanced cervical cancer after primary treatment with chemoradiation therapy. Therefore, we assessed the method of determining the presence of residual disease, the risk of complications, and the survival rate after salvage surgery.

Material And Methods: PubMed, EMBASE, and the Cochrane database were searched from inception up to 6 March 2020. Titles and abstracts were independently assessed by two researchers. Studies were eligible for inclusion when patients had locally advanced cervical cancer with radiologically suspected or histologically confirmed residual disease after chemoradiation therapy, diagnosed with a CT, MRI, or PET-CT scan, or biopsy. Information on complications after salvage surgery and survival outcomes had to be reported. Methodological quality of the articles was independently assessed by two researchers with the Newcastle-Ottawa scale.

Results: Of the 2963 screened articles, six studies were included, representing 220 women. A total of 175 patients were treated with salvage surgery, of whom 27%-100% had residual disease on the surgery specimen. Of the 161 patients treated with salvage surgery based on positive biopsy results, 72%-100% showed residual disease on the surgery specimen. Of the 44 patients treated with salvage surgery based on suspected residual disease on radiology, 27%-48% showed residual disease on the salvage surgery specimen. A total of 105 complications were registered in 175 patients treated with salvage surgery. The overall survival rate after salvage surgery was 69% (mean follow-up period of 24.9 months).

Conclusions: It is necessary to confirm residual disease by biopsy before performing salvage surgery in patients with locally advanced cervical cancer primarily treated with chemoradiation therapy. Salvage surgery only based on radiologically suspected residual disease should be avoided to prevent unnecessary surgery and complications.
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http://dx.doi.org/10.1111/aogs.14093DOI Listing
January 2021

Ovarian cancer prognosis in women with endometriosis: a retrospective nationwide cohort study of 32,419 women.

Am J Obstet Gynecol 2021 03 22;224(3):284.e1-284.e10. Epub 2020 Aug 22.

Department of Obstetrics and Gynecology, Catharina Hospital, Eindhoven, The Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: Contradicting results regarding ovarian cancer prognosis in women with endometriosis have been reported in the literature. Owing to the small sample size of previous studies, larger studies are required to elucidate the role of endometriosis in ovarian cancer prognosis.

Objective: This study aimed to evaluate the survival rate in women with ovarian cancer with or without histologically proven endometriosis in a Dutch population-based cohort.

Study Design: All women with ovarian cancer diagnosed between 1990 and 2015 were identified from the Netherlands Cancer Registry. We linked these women with the Dutch nationwide registry of histopathology and cytopathology (Pathologisch-Anatomisch Landelijk Geautomatiseerd Archief) to identify all women with histologically proven endometriosis. We compared the prognosis of patients with ovarian cancer with and without histologically proven endometriosis. Primary outcome was the overall survival with subgroup analyses stratified by histologic ovarian cancer subtype and stage. Multivariable Cox proportional hazard analysis was used to estimate hazard ratios with 95% confidence intervals.

Results: We included 32,419 patients with ovarian cancer, of whom 1979 (6.1%) had histologically proven endometriosis. The median age of histologic endometriosis diagnosis was 53 years (interquartile range, 46-62). Of all women with ovarian cancer and endometriosis, 81.2% received a diagnosis of synchronous endometriosis and ovarian cancer. The endometriosis cohort was younger at ovarian cancer diagnosis, had more favorable tumor characteristics, and more often had surgical treatment for ovarian cancer than the women without endometriosis. These variables were included in the multivariable model as confounders. Women with histologically proven endometriosis had a significantly better prognosis in both crude and adjusted analyses (hazard ratio, 0.46; 95% confidence interval, 0.43-0.49; P<.0005, and adjusted hazard ratio, 0.89; 95% confidence interval, 0.83-0.95; P<.05, respectively).

Conclusion: Women with ovarian cancer and histologically proven endometriosis had longer overall survival than women with ovarian cancer without endometriosis, even after adjustment for confounders. Future studies on ovarian cancer treatment and prognosis should consider stratifying by endometriosis status to elucidate its role. Furthermore, women diagnosed as having ovarian cancer and concurrent endometriosis should be explained the role of endometriosis in ovarian cancer survival.
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http://dx.doi.org/10.1016/j.ajog.2020.08.056DOI Listing
March 2021

Benefit and burden in the Dutch cytology-based vs high-risk human papillomavirus-based cervical cancer screening program.

Am J Obstet Gynecol 2021 02 13;224(2):200.e1-200.e9. Epub 2020 Aug 13.

Department of Obstetrics and Gynaecology, Catharina Hospital, Eindhoven, the Netherlands; Department of Obstetrics and Gynaecology, GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.

Background: In 2017, the Dutch cervical cancer screening program had replaced the primary cytology-based screening with primary high-risk human papillomavirus-based screening, including the opportunity to participate through self-sampling. Evaluation and balancing benefit (detection of high-grade cervical intraepithelial neoplasia) and burden of screening (unnecessary referrals, invasive diagnostics, and overtreatment) is needed.

Objective: This study aimed to compare the referral rates, detection of high-grade cervical intraepithelial neoplasia, overdiagnosis, and overtreatment in the new high-risk human papillomavirus-based screening program, including physician-sampled and self-sampled material, with the previous cytology-based screening program in the Netherlands.

Study Design: A retrospective cohort study was conducted within the Dutch population-based cervical cancer screening program. Screenees with referrals for colposcopy between 2014 and 2015 (cytology-based screening) and 2017 and 2018 (high-risk human papillomavirus-based screening) were included. Data were retrieved from the Dutch Pathology Registry (PALGA) and compared between the 2 screening programs. The main outcome measures were referral rate, detection of high-grade cervical intraepithelial neoplasia or worse, overdiagnosis (cervical intraepithelial neoplasia grade 1 or less in the histologic specimen), and overtreatment (cervical intraepithelial neoplasia grade 1 or less in the treatment specimen).

Results: Of the women included in the study, 19,109 received cytology-based screening, and 26,171 received high-risk human papillomavirus-based screening. Referral rates increased from 2.5% in cytology-based screening to 4.2% in high-risk human papillomavirus-based screening (+70.2%). Detection rates increased to 46.2% for cervical intraepithelial neoplasia grade 2 or worse, 32.2% for cervical intraepithelial neoplasia grade 3 or worse, and 31.0% for cervical cancer, and overdiagnosis increased to 143.4% with high-risk human papillomavirus-based screening. Overtreatment rates were similar in both screening periods. The positive predictive value of referral for detection of cervical intraepithelial neoplasia grade 2 or worse in high-risk human papillomavirus-based screening was 34.6% compared with 40.2% in cytology-based screening. Women screened through self-sampling were at higher risk of cervical intraepithelial neoplasia grade 2 or worse detection (odds ratio, 1.38; 95% confidence interval, 1.20-1.59) and receiving treatment (odds ratio, 1.31; 95% confidence interval, 1.16-1.48) than those screened through physician-sampling.

Conclusion: Compared with cytology-based screening, high-risk human papillomavirus-based screening increases detection of high-grade cervical intraepithelial neoplasia, with 462 more cervical intraepithelial neoplasia grade 2 or worse cases per 100,000 women but at the expense of 850 more cases per 100,000 women with invasive diagnostics indicating cervical intraepithelial neoplasia grade 1 or less.
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http://dx.doi.org/10.1016/j.ajog.2020.08.026DOI Listing
February 2021

Survival of patients with early-stage cervical cancer after abdominal or laparoscopic radical hysterectomy: a nationwide cohort study and literature review.

Eur J Cancer 2020 07 15;133:14-21. Epub 2020 May 15.

Department of Research & Development, Netherlands Comprehensive Cancer Organisation, Utrecht, the Netherlands.

Aim: Recently, the safety of laparoscopic radical hysterectomy (LRH) has been called into question in early-stage cervical cancer. This study aimed to evaluate overall survival (OS) and disease-free survival (DFS) in patients treated with abdominal radical hysterectomy (ARH) and LRH for early-stage cervical cancer and to provide a literature review.

Methods: Patients diagnosed between 2010 and 2017 with International Federation of Gynaecology and Obstetrics (2009) stage IA2 with lymphovascular space invasion, IB1 and IIA1, were identified from the Netherlands Cancer Registry. Cox regression with propensity score, based on inverse probability treatment weighting, was applied to examine the effect of surgical approach on 5-year survival and calculate hazard ratios (HR) and 95% confidence intervals (CIs). Literature review included observational studies with (i) analysis on tumours ≤4 cm (ii) median follow-up ≥30 months (iii) ≥5 events per predictor parameter in multivariable analysis or a propensity score.

Results: Of the 1109 patients, LRH was performed in 33%. Higher mortality (9.4% vs. 4.6%) and recurrence (13.1% vs. 7.3%) were observed in ARH than LRH. However, adjusted analyses showed similar DFS (89.4% vs. 90.2%), HR 0.92 [95% CI: 0.52-1.60]) and OS (95.2% vs. 95.5%), HR 0.94 [95% CI: 0.43-2.04]). Analyses on tumour size (<2/≥2 cm) also gave similar survival rates. Review of nine studies showed no distinct advantage of ARH, especially in tumours <2 cm.

Conclusion: After adjustment, our retrospective study showed equal oncological outcomes between ARH and LRH for early-stage cervical cancer - also in tumours <2 cm. This is in correspondence with results from our literature review.
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http://dx.doi.org/10.1016/j.ejca.2020.04.006DOI Listing
July 2020

Cervical cancer with ≤5 mm depth of invasion and >7 mm horizontal spread - Is lymph node assessment only required in patients with LVSI?

Gynecol Oncol 2020 Aug 4;158(2):282-286. Epub 2020 May 4.

Department of Obstetrics and Gynaecology, Catherina Cancer Institute, Catharina Hospital, Eindhoven, the Netherlands; Department of Obstetrics and Gynaecology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands.

Objective: Cervical cancer with ≤5 mm depth of invasion and >7 mm horizontal spread is classified FIGO IA instead of FIGO IB in the revised staging system, as horizontal spread is no longer considered. We aimed to determine the incidence of lymph node metastasis (LNM) and, consequently, the necessity of pelvic lymph node assessment.

Methods: Patients diagnosed between January 2015 and May 2019 with cervical cancer FIGO (2009) stage IB with ≤5 mm depth of invasion and >7 mm horizontal spread, were identified from the Netherlands Cancer Registry. Associations between disease-characteristics and lymph node metastasis (LNM), and overall survival, were assessed.

Results: Of 170 patients, six (3.5%) had LNM: 4/53 (7.6%) with adenocarcinoma and 2/117 (1.7%) with squamous cell carcinoma (p = .077). Four-year overall survival was 98.2%. LNM was observed more often in tumours with LVSI (4/43 patients, 9.3%) than without LVSI (2/117 patients, 1.7%) (p = .045). In adenocarcinoma with 3-5 mm depth of invasion LNM rate was 10% (4/40). None of the following tumours were observed with LNM: squamous cell carcinoma without LVSI (0/74); adenocarcinoma with <3 mm depth of invasion (0/13); <3 mm depth of invasion without LVSI (0/36).

Conclusions: Lymph node assessment is essential in any tumour with LVSI or in adenocarcinoma with 3-5 mm depth of invasion. It can be omitted in squamous cell carcinoma without LVSI, in adenocarcinoma with <3 mm depth of invasion and in any tumours without LVSI and with <3 mm depth of invasion.
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http://dx.doi.org/10.1016/j.ygyno.2020.04.705DOI Listing
August 2020

Increased association of ovarian cancer in women with histological proven endosalpingiosis.

Cancer Epidemiol 2020 04 5;65:101700. Epub 2020 Mar 5.

Department of Obstetrics and Gynaecology, Catharina Hospital, Eindhoven, the Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.

Background: Few studies have investigated the possible association between endosalpingiosis and ovarian cancer, therefore we assessed whether there is an association between histological confirmed endosalpingiosis and ovarian cancer.

Methods: We identified all women with a histological diagnosis of endosalpingiosis between 1990 and 2015 from the Dutch nationwide registry of histopathology and cytopathology (PALGA). We used women with a benign dermal nevus as controls. Histology results for cancer of the ovaries, fallopian tubes and peritoneum between January 1990 and July 2017 were retrieved. Incidence rate ratios (IRR) were estimated for ovarian cancer and its subtypes.

Results: We found 2490 women with a histological diagnosis of endosalpingiosis, of which 1005 women 40.4 %) had concurrent endometriosis. The age-adjusted IRR for ovarian cancer in endosalpingiosis patients (including endometriosis) was 43.7 (95 %CI 35.1-54.3). Excluding cases with concurrent endometriosis, resulted in an age-adjusted IRR of 38.8 (95 %CI 29.3-50.4). IRRs were 2.4 (95 %CI 1.4-3.9) and 1.8 (95 %CI 0.8-4.0) respectively when excluding synchronously diagnosed cases. The increased IRRs seem to be caused by an increased risk of clear cell and endometrioid ovarian cancer subtypes.

Conclusions: This study shows an association between histological diagnosed endosalpingiosis and ovarian cancer. The association with endometrioid and clear cell subtypes seems most outspoken. Additionally, this study shows that this association is independent of histological endometriosis diagnosis, making it important for pathologists to report endosalpingiosis accurately and for gynaecologists to be more aware of the increased association of ovarian cancer in women with endosalpingiosis.
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http://dx.doi.org/10.1016/j.canep.2020.101700DOI Listing
April 2020

Incidence of endometrioid and clear-cell ovarian cancer in histological proven endometriosis: the ENOCA population-based cohort study.

Am J Obstet Gynecol 2020 07 23;223(1):107.e1-107.e11. Epub 2020 Jan 23.

Department of Obstetrics and Gynecology, Catharina Hospital, Eindhoven, The Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: Several studies have suggested that endometriosis is associated with an increased risk of ovarian cancer, especially for the clear-cell and endometrioid subtypes. However, previous studies lack sufficient power or diagnostic certainty.

Objective: The objective of the study was to assess the association between histologically proven endometriosis and ovarian cancer in a large population-based cohort study.

Study Design: We identified 131,450 women with a histological diagnosis of endometriosis between 1990 and 2015 from the Dutch nationwide registry of histopathology and cytopathology (PALGA). For the control cohort 132,654 women with a benign dermal nevus were matched on age and inclusion year with the endometriosis cases. Histological diagnoses of ovarian, fallopian tubes, and peritoneal cancers between January 1990 and July 2017 were retrieved. Incidence rate ratios were estimated for ovarian cancer and its subtypes for the whole follow-up period as well as for women with more than 1 person-year at risk.

Results: We found a crude incidence rate ratio of 4.79 (95% confidence interval, 4.33-5.31) and an age-adjusted incidence rate ratio of 7.18 (95% confidence interval, 6.17-8.36) for ovarian cancer overall. Endometrioid and clear-cell ovarian cancer had the highest age-adjusted incidence rate ratio of 29.06 (95% confidence interval, 20.66-40.87) and 21.34 (95% confidence interval, 14.01-32.51), respectively. Median age at ovarian cancer diagnosis was 56 years (interquartile range, 49-63) for the endometriosis cohort and 60 years (interquartile range, 53-67) for the nevus cohort, (P < .05). After excluding women with less than 1 person-year at risk following an endometriosis diagnosis, we found a crude incidence rate ratio of 1.04 (95% confidence interval, 0.91-1.19) and an age-adjusted incidence rate ratio of 1.08 (95% confidence interval, 0.87-1.35) for ovarian cancer overall. However, statistically significant age-adjusted incidence rate ratios of 2.29 (95% confidence interval, 1.24-4.20) for clear-cell ovarian cancer and 2.56 (95% confidence interval, 1.47-4.47) for endometrioid ovarian cancer were found.

Conclusion: A significantly higher incidence of clear-cell and endometrioid ovarian cancer was found in women with histologically proven endometriosis. Additionally, we found an increased incidence of all ovarian cancer subtypes in histologically proven endometriosis; however, in many of these women, endometriosis and ovarian cancer were diagnosed synchronously after the average menopausal age, which may suggest that the risk of ovarian cancer in endometriosis patients remains, even when clinical endometriosis symptoms are no longer present.
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http://dx.doi.org/10.1016/j.ajog.2020.01.041DOI Listing
July 2020

The risk of cervical cancer after cervical intraepithelial neoplasia grade 3: A population-based cohort study with 80,442 women.

Gynecol Oncol 2020 04 20;157(1):195-201. Epub 2020 Jan 20.

Department of Obstetrics and Gynecology, Catharina Hospital, PO Box 1350, 5602ZA Eindhoven, the Netherlands. Electronic address:

Objective: To estimate the risk of cervical cancer in women with a history of cervical intraepithelial neoplasia (CIN) grade 3 and to review the compliance with post-treatment follow-up.

Methods: A population-based retrospective cohort study including 80,442 women with a median follow-up of 15.8 years, and 1,278,297 person years. Women with CIN3 between 1990 and 2010 were identified from the Dutch Pathology Registry (PALGA) and linked to the general female population from the Netherlands Cancer Registry. Cases of recurrent CIN3 and cervical cancer, defined as occurrence minimally two years post-treatment, were identified until 2016. Standardized incidence ratios (SIRs) were calculated for the risk of cervical cancer.

Results: 1554 women (1.9%) developed recurrent CIN3 and 397 women (0.5%) cervical cancer. Women with CIN3 were associated with a twofold increased risk of cervical cancer (SIR 2.29; 95%CI 2.07-2.52) compared with the general female population. Women aged ≥50 years during CIN3 diagnosis had a sevenfold and women with recurrent CIN3 a ninefold increased risk of developing cervical cancer. The increased risk up to 20 years of follow-up seems to be mostly attributable to ageing. 37.0% of women who developed cervical cancer after CIN3 did not complete the advised post-treatment follow-up.

Conclusions: Women with CIN3 have a long-lasting twofold increased risk of developing cervical cancer, even when they complete the post-treatment follow-up and adhere to the regular screening program. This risk increases with CIN3 diagnosis at older age, further ageing during follow-up and in women with recurrent CIN3. Studies on optimizing follow-up strategies are warranted.
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http://dx.doi.org/10.1016/j.ygyno.2020.01.023DOI Listing
April 2020

Short-term surgical complications after radical hysterectomy-A nationwide cohort study.

Acta Obstet Gynecol Scand 2020 07 6;99(7):925-932. Epub 2020 Feb 6.

Department of Research & Development, Netherlands Comprehensive Cancer Organization (IKNL), Utrecht, the Netherlands.

Introduction: Centralization has, among other aspects, been argued to have an impact on quality of care in terms of surgical morbidity. Next, monitoring quality of care is essential in identifying areas of improvement. This nationwide cohort study was conducted to determine the rate of short-term surgical complications and to evaluate its possible predictors in women with early-stage cervical cancer.

Material And Methods: Women diagnosed with early-stage cervical cancer, 2009 FIGO stages IB1 and IIA1, between 2015 and 2017 who underwent radical hysterectomy with pelvic lymphadenectomy in 1 of the 9 specialized medical centers in the Netherlands, were identified from the Netherlands Cancer Registry. Women were excluded if primary treatment consisted of hysterectomy without parametrial dissection or radical trachelectomy. Women in whom radical hysterectomy was aborted during the procedure, were also excluded. Occurrence of intraoperative and postoperative complications and type of complications, developing within 30 days after surgery, were prospectively registered. Multivariable logistic regression analysis was used to identify predictors of surgical complications.

Results: A total of 472 women were selected, of whom 166 (35%) developed surgical complications within 30 days after radical hysterectomy. The most frequent complications were urinary retention with catheterization in 73 women (15%) and excessive perioperative blood loss >1000 mL in 50 women (11%). Open surgery (odds ratio [OR] 3.42; 95% CI 1.73-6.76), chronic pulmonary disease (OR 3.14; 95% CI 1.45-6.79), vascular disease (OR 1.90; 95% CI 1.07-3.38), and medical center (OR 2.83; 95% CI 1.18-6.77) emerged as independent predictors of the occurrence of complications. Body mass index (OR 0.94; 95% CI 0.89-1.00) was found as a negative predictor of urinary retention. Open surgery (OR 36.65; 95% CI 7.10-189.12) and body mass index (OR 1.15; 95% CI 1.08-1.22) were found to be independent predictors of excessive perioperative blood loss.

Conclusions: Short-term surgical complications developed in 35% of the women after radical hysterectomy for early-stage cervical cancer in the Netherlands, a nation with centralized surgical care. Comorbidities predict surgical complications, and open surgery is associated with excessive perioperative blood loss.
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http://dx.doi.org/10.1111/aogs.13812DOI Listing
July 2020

Oral contraceptive and intrauterine device use and the risk of cervical intraepithelial neoplasia grade III or worse: a population-based study.

Eur J Cancer 2020 01 21;124:102-109. Epub 2019 Nov 21.

Department of Pathology, Radboud university medical center, PO Box 9101, 6500HB, Nijmegen, the Netherlands; PALGA, Randhoeve 225a, 3995 GA, Houten, the Netherlands. Electronic address:

Objective: Hormonal contraceptive use has been associated with the development of cervical cancer, although inconsistent results are reported on the association with intrauterine device (IUD) use. The aim of this study was to evaluate the association between the type of contraceptive use and the development of cervical intraepithelial neoplasia grade III or worse (CIN3+).

Methods: A retrospective population-based cohort study including women aged 29-44 years attending the cervical cancer screening program with normal cytology between 2005 and 2009 identified from the Dutch Pathology Registry. Subgroups with at least 5 years registered use of an oral contraceptive (OC) or IUD were compared with non-users. Risk ratios of CIN3+ were estimated per contraceptive type.

Results: 702,037 women were included with a median follow-up of 9.7 years, of which 6705 (0.96%) and 559 (0.08%) women developed CIN3 and cervical cancer, respectively. IUD use was associated with an increased risk of developing CIN3+ (risk ratio (RR) 1.51, 95% confidence interval (CI) 1.32-1.74), and OC use was associated with an increased risk of developing CIN3+ (RR 2.77, 95%CI 2.65-3.00) and cervical cancer (RR 2.06, 95%CI 1.52-2.79). The risk of developing CIN3+ and cervical cancer was higher for OC users compared with IUD users (RR 1.83, 95%CI 1.60-2.09 and RR 1.70, 95%CI 1.00-2.90, respectively).

Conclusions: Both OC use and IUD use were associated with an increased risk of developing CIN3+. However, for women with a contraceptive wish, an IUD seems safer than an OC as the risk of developing CIN3+ and cervical cancer was higher for OC users.
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http://dx.doi.org/10.1016/j.ejca.2019.10.009DOI Listing
January 2020

Risk prediction of cervical abnormalities: The value of sociodemographic and lifestyle factors in addition to HPV status.

Prev Med 2020 01 19;130:105927. Epub 2019 Nov 19.

Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands; Dutch Expert Centre for Screening, Nijmegen, the Netherlands.

High-risk human papillomavirus (hrHPV) assessment as a primary screening test improves sensitivity but decreases specificity. Determining risk for cervical abnormalities and adapting policy accordingly may improve the balance between screening benefits and harms. Our aim is to assess the value of factors other than HPV in prediction of cervical abnormalities. Data from a Dutch prospective cohort were used. Women aged 18-29 years, not yet eligible for screening, were included in 2007. Data collection consisted of a questionnaire and a cervicovaginal self-sample. Linkage with PALGA (pathology database) was performed in 2017. The analyses included 1483 women. The full model, including sociodemographic and lifestyle factors, was compared to the null model, including baseline HPV only. The outcome of interest was cervical intraepithelial neoplasia 2 or worse (CIN2+). There were 86 women with CIN2+. Baseline hrHPV status was an important predictor (OR = 5.20, 95%CI = 3.27-8.27). The area under the ROC curve (AUC) of the null model was 0.67 (95%CI = 0.61-0.72). The full model had a slightly higher AUC of 0.73 (95%CI = 0.67-0.79). Bootstrap validation indicated that overfitting was present. This exploratory study has confirmed that a single hrHPV measurement is a strong predictor of cervical abnormalities, and additional risk factors in young women appeared to have limited added value. However, prediction based on hrHPV only does leave room for improvement. Future studies should therefore focus on women in the screening age range and search for other predictors to further enhance risk prediction. Adapting policy based on risk may eventually help optimise screening performance.
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http://dx.doi.org/10.1016/j.ypmed.2019.105927DOI Listing
January 2020

Clinical practice variation and overtreatment risk in women with abnormal cervical cytology in the Netherlands: two-step versus see-and-treat approach.

Am J Obstet Gynecol 2020 04 21;222(4):354.e1-354.e10. Epub 2019 Oct 21.

Department of Obstetrics and Gynecology, Catharina Hospital, Eindhoven, Netherlands.

Background: Only a few small studies have compared the 2-step method (biopsy followed by treatment) with a see-and-treat (immediate treatment) approach in women both low-grade or high-grade referral cytology. The clinical practice variation in the Netherlands has not been reviewed before.

Objectives: To determine overtreatment rates in the 2-step versus see-and-treat approach in women referred for colposcopy because of abnormal cytology results, and to evaluate clinical practice variation in the Netherlands.

Materials And Methods: This was a population-based retrospective cohort study including 36,581 women with a histologic result of the cervix identified from the Dutch Pathology Registry (PALGA) between 2016 and 2017. Odds ratios for overtreatment, defined primarily as cervical intraepithelial neoplasia grade 1 or less, were determined for the 2-step and see-and-treat approach in relation to age, high-risk human papillomavirus status, and referral cytology.

Results: Of the included women 10,713 women (29.3%) received the 2-step method; 6,851 women (18.7%) underwent see-and-treat; and 19,017 women (52.0%) received conservative management after colposcopy with histologic assessment with cytologic follow-up or another type of treatment. Despite the existence of a national guideline advising see-and-treat only in case of suspected high-grade disease in women who have completed their childbearing, there is a wide practice variation between the 2 strategies in the Netherlands, with 7.0-88.3% of the women receiving see-and-treat per laboratory. The median time between cytology and treatment was 1-2 months (range, 0-12 months) in women receiving see-and-treat and the 2-step method, respectively. A total of 4119 women (23.5%) were overtreated, with older women, high-risk human papillomavirus-negative women, and women with low-grade cytology results being more likely to be overtreated. Women with low-grade cytology results and see-and-treat were associated with a higher overtreatment rate than women receiving the 2-step method (65.0% [1414 of 2174] versus 32.1% [1161 of 3613], respectively; odds ratio, 3.34; 95% confidence interval, 2.92-3.82). However, in women with high-grade cytology results, see-and-treat was inversely associated with overtreatment (11.3% [529 of 4677] versus 14.3% [1015 of 7100], respectively; odds ratio, 0.68; 95% confidence interval, 0.58-0.81).

Conclusion: A see-and-treat approach is justified only in women with high-grade cytology results who have completed their childbearing. There is a wide practice variation between the 2 strategies in the Netherlands, and gynecologists should adhere to the guideline to prevent overtreatment.
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http://dx.doi.org/10.1016/j.ajog.2019.10.004DOI Listing
April 2020

RNA-based high-risk HPV genotyping and identification of high-risk HPV transcriptional activity in cervical tissues.

Mod Pathol 2020 04 19;33(4):748-757. Epub 2019 Sep 19.

Department of Biochemistry, Radboud Institute for Molecular Life Sciences, 6525 GA, Nijmegen, The Netherlands.

Nearly all cervical cancers are initiated by a persistent infection with one of the high-risk human papillomaviruses (high-risk HPV). High-risk HPV DNA testing is highly sensitive but cannot distinguish between active, productive infections and dormant infections or merely deposited virus. A solution for this shortcoming may be the detection of transcriptional activity of viral oncogenes instead of mere presence of high-risk HPVs. In this study, fresh-frozen cervical tissues (n = 22) were subjected to high-risk HPV DNA detection using the line probe assay and to targeted RNA next-generation sequencing using single-molecule molecular inversion probes. Targeted RNA sequencing was applied for (1) RNA-based genotyping of high-risk HPV, giving information on specific HPV-subtype (2) discrimination of E2, E6, and E7 transcripts and (3) discovery of possible non-HPV cancer biomarkers. Data were analyzed using computational biology. Targeted RNA sequencing enabled reliable genotyping of high-risk HPV subtypes and allowed quantitative detection of E2, E6, and E7 viral gene expression, thereby discriminating cervical lesions from normal cervical tissues. Moreover, targeted RNA sequencing identified possible cervical cancer biomarkers other than high-risk HPV. Interestingly, targeted RNA sequencing also provided high-quality transcription profiles from cervical scrape samples, even after 1 week of dry storage or storage in Preservcyt fixative. This proof of concept study shows that targeted RNA sequencing can be used for high-risk HPV genotyping and simultaneous detection of high-risk HPV gene activity. Future studies are warranted to investigate the potential of targeted RNA sequencing for risk assessment for the development of cervical lesions, based on molecular analysis of cervical scrapes.
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http://dx.doi.org/10.1038/s41379-019-0369-7DOI Listing
April 2020

Development of the Patient's Experience and Attitude Colposcopy Eindhoven Questionnaire (PEACE-q).

BMC Health Serv Res 2019 Aug 20;19(1):589. Epub 2019 Aug 20.

Department of Obstetrics and Gynaecology, Catharina Hospital, Eindhoven, The Netherlands.

Background: No validated instruments for the evaluation of patient satisfaction in colposcopy do exist. Therefore, this study reports on the development of a Patient's Experience and Attitude to Colposcopy questionnaire.

Methods: Patients who recently received colposcopy participated in a focus group. A panel of experts evaluated the transcriptions and agreed on a 15-item draft questionnaire. The draft questionnaire was completed by 68 women who subsequently came for a colposcopy. For construct validation, Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA) were performed as well as reliability analysis. Concurrent validity was assessed with the 4-item Patient Health questionnaire (PHQ-4).

Results: Construct validation resulted in an 8-item patient perception scale with good psychometric properties (Cronbach's alpha: 0.76) and excellent model fit. Two subscales could be discriminated: patient procedure perception scale (alpha: 0.89) and caregiver attitude perception scale (alpha: 0.71). Both subscales intercorrelated moderately (r = 0.28, p = 0.045). The subscale patient perception correlated significantly with the PHQ-4 scale and its anxiety subscale, not with the depression subscale.

Conclusions: We developed a Patient's Experience and Attitude to Colposcopy questionnaire with adequate psychometric properties. Future application in out-patient clinics should further evaluate its clinical relevance.
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http://dx.doi.org/10.1186/s12913-019-4425-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702716PMC
August 2019

Systemic adverse events in imiquimod use for cervical intraepithelial neoplasia - A case series.

Case Rep Womens Health 2019 Jan 6;21:e00105. Epub 2019 Mar 6.

Department of Obstetrics and Gynaecology, Catharina Hospital, Eindhoven, the Netherlands.

Treatment for cervical intraepithelial neoplasia (CIN) often consists of an excisional procedure. However, less invasive treatment methods have been explored, such as topical treatment with imiquimod cream. Imiquimod has been proven to be effective in the regression of vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VAIN). Previous studies have investigated the effect of imiquimod in CIN and showed well tolerated adverse effects. During a current study in the Netherlands, a number of adverse events have occurred. This case series presents a selection of these. Gynaecologists should be aware of the possible adverse effects of topical treatment with imiquimod cream.
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http://dx.doi.org/10.1016/j.crwh.2019.e00105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411488PMC
January 2019

Post-Colposcopy Management and Progression Predictors of Biopsy-Proven CIN1 in Women Under 25 Years.

J Obstet Gynaecol Can 2019 Mar 27;41(3):292-299. Epub 2018 Oct 27.

Department of Obstetrics and Gynecology, Queen Elizabeth II Health Sciences Centre, Halifax, NS.

Objective: The post-colposcopy management and outcome of cervical intraepithelial neoplasia grade 1 (CIN1) in women under 25 years of age was reviewed, and potential predictors for progression were identified.

Methods: Women under 25 with biopsy-proven CIN1 between January 1, 2010, and December 31, 2012 who were seen in the colposcopy clinic at the Queen Elizabeth II Hospital in Halifax, Nova Scotia were retrospectively reviewed. The regression, persistence, and progression rates of CIN1 were evaluated, and the relevant behavioural and biologic factors were reviewed.

Results: Of the 326 women with a biopsy-proven CIN1, 234 (71.8%) women returned to the regular screening program, and 92 women remained in the colposcopy clinic during follow-up, with a median follow-up time of 26 months. Sixty-two percent of the women had no cervical abnormality, 23.6% of the women had persistent CIN1, and 14.4% of the women showed progression. Eight percent showed progression to CIN2 with a median time of 13 months, whereas 6.4% showed progression to CIN3+ within a median time of 17.5 months. The extent of the lesion (hazard ratio 2.33; 95% CI 1.17-4.64, P = 0.02) and the Pap test result at the initial visit (hazard ratio 2.16; 95% CI 1.22-3.82, P = 0.008) were significantly associated with progression to CIN2+.

Conclusion: On the basis of the 6% risk of CIN3+ and the median time to progression of 17.5 months, follow-up with cytology at 12 months seems acceptable. The extent of the lesion and the Pap test result at the initial visit were identified as risk factors for progression of CIN1.
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http://dx.doi.org/10.1016/j.jogc.2018.06.021DOI Listing
March 2019

Management and treatment of cervical intraepithelial neoplasia in the Netherlands after referral for colposcopy.

Acta Obstet Gynecol Scand 2019 06 27;98(6):737-746. Epub 2019 Feb 27.

Department of Public Health, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.

Introduction: The aim of this study was to describe trends in the diagnosis and treatment of women referred from the national screening program with cervical intraepithelial neoplasia (CIN) in the Netherlands, and to compare these trends with national guidelines and identify potential areas for improvement for the new primary high-risk HPV screening program.

Material And Methods: We conducted a population-based cohort study using data from the Dutch pathology archive. Women aged 29-63 years who took part in the Dutch cervical screening program between 1 January 2005 and 31 December 2014 were selected. Three referral groups were identified: direct referrals and those referred after either one (first indirect referrals) or two (second indirect referrals) repeat cytology tests, totaling 85 239 referrals for colposcopy. The most invasive management technique and the most severe diagnosis of each screening episode was identified. Rates of management techniques were calculated separately by referral type, highest CIN diagnosis and age group.

Results: In all, 85.1% of CIN 3 lesions were treated with excision (either large excision or hysterectomy) and 26.4% of CIN 1 lesions were treated with large excision. Rates of overtreatment (CIN 1 or less) in see-and-treat management were higher for indirect referrals than for direct referrals and increased with age. Large excision rates increased with CIN diagnosis severity.

Conclusions: Despite guideline recommendations not to treat, CIN 1 lesions were treated in just over 25% of cases and approximately 15% of CIN 3 lesions were possibly undertreated. Given the expected increase in CIN detection in the new primary high-risk HPV screening program, reduction in CIN 1 treatment and CIN 2 treatment in younger women is needed to avoid an increase in potential harm.
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http://dx.doi.org/10.1111/aogs.13547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593855PMC
June 2019

Performance of human papillomavirus testing on self-collected versus clinician-collected samples for the detection of cervical intraepithelial neoplasia of grade 2 or worse: a randomised, paired screen-positive, non-inferiority trial.

Lancet Oncol 2019 02 15;20(2):229-238. Epub 2019 Jan 15.

Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Epidemiology and Biostatistics, Amsterdam Public Health, Amsterdam, Netherlands. Electronic address:

Background: Human papillomavirus (HPV) testing on self-collected samples is a potential alternative to HPV testing on clinician-collected samples, but non-inferiority of its clinical accuracy remains to be assessed in the regular screening population. The IMPROVE study was done to evaluate the clinical accuracy of primary HPV testing on self-collected samples within an organised screening setting.

Methods: In this randomised, non-inferiority trial, women aged 29-61 years were invited to participate in the study as part of their regular screening invitation in the Netherlands. Women who provided informed consent were randomly allocated (1:1, with a block size of ten stratified by age) to one of two groups: a self-sampling group, in which women were requested to collect their own cervicovaginal sample using an Evalyn Brush (Rovers Medical Devices BV, Oss, Netherlands); or a clinician-based sampling group, in which samples were collected by a general practitioner with a Cervex-Brush (Rovers Medical Devices BV). All samples were tested for HPV using the clinically validated GP5+/6+ PCR enzyme immunoassay (Labo Biomedical Products BV, Rijswijk, Netherlands). HPV-positive women in both groups were retested with the other collection method and triaged by cytology and repeat cytology in accordance with current Dutch screening guidelines. Primary endpoints were detection of cervical intraepithelial neoplasia (CIN) of grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+). Non-inferiority of HPV testing on self-collected versus clinician-collected samples was evaluated against a margin of 90% for the relative sensitivity and 98% for the relative specificity. This study is registered at the Dutch Trial register (NTR5078) and has been completed.

Findings: Of the 187 473 women invited to participate, 8212 were randomly allocated to the self-sampling group and 8198 to the clinician-based sampling group. After exclusion of women who met the exclusion criteria or who did not return their sample, 7643 women were included in the self-sampling group and 6282 in the clinician-based sampling group. 569 (7·4%) self-collected samples and 451 (7·2%) clinician-collected samples tested positive for HPV (relative risk 1·04 [95% CI 0·92-1·17]). Median follow-up duration for HPV-positive women was 20 months (IQR 17-22). The CIN2+ sensitivity and specificity of HPV testing did not differ between self-sampling and clinician-based sampling (relative sensitivity 0·96 [0·90-1·03]; relative specificity 1·00 [0·99-1·01]). For the CIN3+ endpoint, relative sensitivity was 0·99 (0·91-1·08) and relative specificity was 1·00 (0·99-1·01).

Interpretation: HPV testing done with a clinically validated PCR-based assay had similar accuracy on self-collected and clinician-collected samples in terms of the detection of CIN2+ or CIN3+ lesions. These findings suggest that HPV self-sampling could be used as a primary screening method in routine screening.

Funding: Ministry of Health, Welfare, and Sport (Netherlands), and the European Commission.
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http://dx.doi.org/10.1016/S1470-2045(18)30763-0DOI Listing
February 2019

Justifying conservative management of CIN2 in women younger than 25 years - A population-based study.

Gynecol Oncol 2019 01 7;152(1):82-86. Epub 2018 Nov 7.

Division of Gynecologic Oncology, Queen Elizabeth II Health Sciences Centre, 5820 University Avenue, Halifax, NS B3H 1Y9, Canada. Electronic address:

Objective: In 2012, the joint clinical practice guideline from the Society of Obstetricians and Gynaecologists of Canada (SOGC) changed from immediate treatment to a more conservative management of Cervical Intraepithelial Neoplasia (CIN) grade 2 in young women. In this study, the outcomes before and after this management change were reviewed in Nova Scotia, Canada.

Methods: A retrospective population-based cohort study was performed among women younger than 25 years with biopsy-proven CIN2, who were diagnosed in one of the colposcopy clinics in Nova Scotia between 2010 and 2014. Regression and progression rates were compared pre- and post-guideline changes.

Results: Of the 636 women included in the study, 286 women were diagnosed with CIN2 before and 350 women after the management in Nova Scotia was changed. After implementation of the 2012 guidelines patients were more likely to receive conservative management (78.6% versus 44.1%; p < 0.001); which differs from the patients who underwent treatment during follow-up prior to the change in guidelines (73.4% versus 38.9%; p < 0.001). Regression occurred in 73.1% of all women, but women seen in the post-guideline change period had a higher regression rate and lower progression rate (p < 0.05). Histologic results from treatment specimen did not show a significant difference in low-grade or high-grade lesions before or after the guideline had been changed (p = 0.59).

Conclusion: Conservative management seems a safe and justified approach for women younger than 25 years with CIN2.
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http://dx.doi.org/10.1016/j.ygyno.2018.10.038DOI Listing
January 2019

Screening for persistent high-risk HPV infections may be a valuable screening method for young women; A retrospective cohort study.

PLoS One 2018 24;13(10):e0206219. Epub 2018 Oct 24.

Department of Obstetrics and Gynaecology, Radboud university medical center, Nijmegen, the Netherlands.

Introduction: Screening of young women is often discouraged because of the high risk of unnecessary diagnostics or overtreatment. Multiple countries therefore use cytology instead of high risk human papillomavirus (hrHPV)-testing as screening method for young women because of the limited specificity of hrHPV-testing. The objective of this study was to investigate how hrHPV screening before the age of 30, can be used to reduce the future prevalence of high-grade cervical lesions in young women.

Methods: We retrospectively analyzed follow-up data from a cohort study on HPV prevalence in unscreened Dutch women aged 18-29 years. Women performed multiple self-collected cervico-vaginal samples for HPV detection and genotyping. At least one valid cervical pathology result was obtained from 1,018 women. Women were categorized as hrHPV negative, cleared- or persistent hrHPV infection. Anonymized follow-up data for each group was obtained. Composite outcome measures were defined as; normal, low-grade squamous intraepithelial lesion (LSIL) or high-grade squamous intraepithelial lesion (HSIL). The association between prior hrHPV status and cytology and histology outcome was analyzed.

Results: After exclusion, a pathology result was registered for 962 women. The prevalence of HSIL was 19.3% in women with a persistent HPV infection at a younger age. This is significantly higher (p<0,001) compared with the HSIL prevalence of 1.5% in HPV-negative women, and 3.1% (n = 8) in women who cleared the hrHPV infection in the past.

Conclusion: Women with a persistent hrHPV infection in their 20s, show an increased prevalence of HSIL lesions in their early 30s. Screening for persistent hrHPV infections, instead of cytology screening before the age of 30, can be used to reduce the future prevalence of cervical cancer in young women.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206219PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200272PMC
April 2019

Defining hrHPV genotypes in cervical intraepithelial neoplasia by laser capture microdissection supports reflex triage of self-samples using HPV16/18 and FAM19A4/miR124-2 methylation.

Gynecol Oncol 2018 11 13;151(2):311-318. Epub 2018 Sep 13.

Department of Medical Microbiology, Radboud university medical center, Nijmegen, the Netherlands.

Objective: HPV16/18 genotyping and detection of hypermethylation of human cell genes involved in cervical oncogenesis have shown promising results in triage of high-risk HPV (hrHPV)-screen positive women on cervical smears. These tests can be performed on self-samples, which contain cervical and vaginal cells. We studied whether a self-sample represents the hrHPV type causing the worst cervical lesion and whether any differences in hypermethylation of FAM19A4/miR124-2 exist between CIN lesions caused by different hrHPV types. These results have important implications for reflex triage of self-samples.

Methods: Correlation between genotype found on self-sample using GP5+/6+-PCR-EIA-LMNX and causative hrHPV genotype in the worst lesion on histology was studied using laser capture microdissection (LCM)-SPF10-PCR (N = 152). Hypermethylation of FAM19A4/miR124-2 in the self-sample was tested in a quantitative methylation specific PCR and compared between lesions caused by HPV16/18 and other hrHPV genotypes.

Results: Causative hrHPV genotype of the worst lesion (CIN1, CIN2, CIN3, invasive cervical cancer) was detected on self-sample in 93.4%. HPV16 was the most frequently found genotype on self-sampling (39.2%, 73/186) and causative genotype in CIN3+ (51.4%, 38/74, all detected on self-sample). There were no differences in the percentages of positive FAM19A4/miR124-2 methylation assays between lesions caused by HPV16/18 (73.8% in CIN3+) or other hrHPV genotypes (66.7% in CIN3+) (p = 0.538).

Conclusions: Our results show that hrHPV genotypes found on self-sample were a good representation of hrHPV in the worst CIN lesion and that methylation testing on self-sample for detection of CIN3+ was not significantly different between lesions caused by HPV16/18 and other hrHPV genotypes.
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http://dx.doi.org/10.1016/j.ygyno.2018.09.006DOI Listing
November 2018

Identification and Validation of a 3-Gene Methylation Classifier for HPV-Based Cervical Screening on Self-Samples.

Clin Cancer Res 2018 07 9;24(14):3456-3464. Epub 2018 Apr 9.

Cancer Center Amsterdam, Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.

Offering self-sampling of cervico-vaginal material for high-risk human papillomavirus (hrHPV) testing is an effective method to increase the coverage in cervical screening programs. Molecular triage directly on hrHPV-positive self-samples for colposcopy referral opens the way to full molecular cervical screening. Here, we set out to identify a DNA methylation classifier for detection of cervical precancer (CIN3) and cancer, applicable to lavage and brush self-samples. We determined genome-wide DNA methylation profiles of 72 hrHPV-positive self-samples, using the Infinium Methylation 450K Array. The selected DNA methylation markers were evaluated by multiplex quantitative methylation-specific PCR (qMSP) in both hrHPV-positive lavage ( = 245) and brush ( = 246) self-samples from screening cohorts. Subsequently, logistic regression analysis was performed to build a DNA methylation classifier for CIN3 detection applicable to self-samples of both devices. For validation, an independent set of hrHPV-positive lavage ( = 199) and brush ( = 287) self-samples was analyzed. Genome-wide DNA methylation profiling revealed 12 DNA methylation markers for CIN3 detection. Multiplex qMSP analysis of these markers in large series of lavage and brush self-samples yielded a 3-gene methylation classifier ( and ). This classifier showed a very good clinical performance for CIN3 detection in both lavage (AUC = 0.88; sensitivity = 74%; specificity = 79%) and brush (AUC = 0.90; sensitivity = 88%; specificity = 81%) self-samples in the validation set. Importantly, all self-samples from women with cervical cancer scored DNA methylation-positive. By genome-wide DNA methylation profiling on self-samples, we identified a highly effective 3-gene methylation classifier for direct triage on hrHPV-positive self-samples, which is superior to currently available methods. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053041PMC
July 2018

Para-aortic lymphadenectomy in advanced stage cervical cancer, a protocol for comparing safety, feasibility and diagnostic accuracy of surgical staging versus PET-CT; PALDISC trial.

Pilot Feasibility Stud 2018 4;4:27. Epub 2018 Jan 4.

Department of Gynaecology, Radboud University Medical Centre, Radboudumc Institute for Health Sciences, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands.

Background: Currently, a PET-CT is used to assess the need for extended field radiotherapy of para-aortic lymph nodes (PALN) in International Federation of Gynaecology and Obstetrics (FIGO) stage IB2, IIA2-IVA (locally advanced stage) cervical cancer. A small study established a sensitivity and specificity estimate for PALN metastases of 50% (95% CI; 7-93%) and 83% (95% CI; 52-98%), respectively. Surgical staging of PALN may lead to a higher diagnostic accuracy. However, surgical staging of para-aortic lymph nodes in locally advanced stage cervical cancer is not common practice. Therefore, a phase 2 randomised controlled trial is needed to assess its safety and feasibility.

Methods/design: In addition to standard imaging (MRI or CT scan) with PET-CT, 30 adult women with FIGO stage IB2, IIA2-IVA cervical cancer will be randomised to receive either surgical staging or usual PET-CT staging. Administering extended field radiotherapy will be based on lymphadenectomy results for the intervention group and on the PET-CT results for the control group. Follow-up visits at 0, 3, 6, 9 and 12 months will assess health-related quality of life and progression-free survival.Primary safety and feasibility outcomes of surgical staging will be assessed by calculating means with 95% confidence intervals for duration of surgery, number of complications, blood loss, nodal yield after para-aortic lymphadenectomy and treatment delay due to surgical staging. Secondary patient-centred outcomes on quality of life and first year survival will be documented and compared between the two groups. Estimates of sensitivity, specificity and negative and positive predictive values of MRI, PET-CT and surgical staging will be presented with 95% CI.. All analysis will be performed according to the intention to treat principle.

Discussion: This study will assess safety and feasibility, expressed as the number and severity of complications, effect on quality of life and the treatment delay due to surgically staging para-aortic lymph nodes in locally advanced cervical cancer. It will provide insight in the diagnostic accuracy of the PET-CT and detection rate of missed (micro)metastases due to surgical staging. This information will be used to assess the necessity for a phase 3 study on the diagnostic accuracy of the PET-CT and surgical staging. If a phase 3 study is deemed necessary, current data can be used for sample size calculation of such a phase 3 study.

Trial Registration: Nederlands Trial Register/Dutch Trial Registry (www.trialregister.nl), NTR4922. Registered on 24 November 2014.
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http://dx.doi.org/10.1186/s40814-017-0218-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755440PMC
January 2018

The effect of video information on anxiety levels in women attending colposcopy: a randomized controlled trial.

Acta Oncol 2017 Dec 1;56(12):1728-1733. Epub 2017 Aug 1.

a Department of Obstetrics and Gynaecology , Radboud University Medical Center , Nijmegen , The Netherlands.

Objective: The aim was to investigate whether additional information, in video form, reduces anxiety, depression and pain levels in women referred for colposcopy.

Material And Methods: Between September 2012 and March 2015, 136 patients referred for colposcopy were randomized into two study arms. Group A received video information in addition to the regular information leaflet, and group B (control group) received only the regular information leaflet. The patients were requested to complete standardized online questionnaires. The first online questionnaire (T1) was pre-randomization, and was completed at home, 5 days prior to the appointment. The second online questionnaire (T2) was completed directly before the colposcopy appointment, and the last online questionnaire (T3) was completed directly following colposcopy at the out-patient clinic. The questionnaires included the Spielberger State-Trait Anxiety Inventory (STAI), the Hospital Anxiety and Depression Scale (HADS), and the Numeric Rating Scale (NRS) to assess pain.

Results: The STAI state anxiety score was high (44.6), but there was no significant difference in STAI, HADS and NRS between the two groups at the three measuring points. A post hoc analysis showed that women with a generally higher baseline anxiety trait had significantly lower HADS anxiety levels following video information.

Conclusions: Additional information (video) before colposcopy did not significantly reduce anxiety, depression, and expected or experienced pain, as measured by the STAI, HADS and NRS in patients attending their first colposcopy appointment. However, most patients positively appreciated the video information, which may reduce the anxiety of extremely anxious patients.
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http://dx.doi.org/10.1080/0284186X.2017.1355108DOI Listing
December 2017

Long-Lasting Increased Risk of Human Papillomavirus-Related Carcinomas and Premalignancies After Cervical Intraepithelial Neoplasia Grade 3: A Population-Based Cohort Study.

J Clin Oncol 2017 Aug 25;35(22):2542-2550. Epub 2017 May 25.

Renée M.F. Ebisch, Dominiek W.E. Rutten, Joanna IntHout, Willem J.G. Melchers, Leon F.A.G. Massuger, Johan Bulten, Ruud L.M. Bekkers, and Albert G. Siebers, Radboud University Medical Center, Nijmegen; and Ruud L.M. Bekkers, Catharina Hospital Eindhoven, Eindhoven, the Netherlands.

Purpose The aim of this study was to determine the risk of human papillomavirus (HPV)-related carcinomas and premalignancies in women diagnosed with cervical intraepithelial neoplasia grade 3 (CIN3). Knowledge of this risk is important to preventing the development and progression of other HPV-related premalignancies and carcinomas, by considering prophylactic HPV vaccination and/or by paying increased attention to other HPV-related carcinomas and premalignancies when CIN3 is identified. Methods Women diagnosed with a CIN3 between 1990 and 2010 were identified from the Dutch nationwide registry of histopathology and cytopathology (PALGA) and matched with a control group of women without CIN3. Subsequently, all cases of high-risk (hr) HPV-associated high-grade lesions and carcinomas in the anogenital region and oropharynx between 1990 and 2015 were extracted. Incidence rate ratios were estimated for carcinomas and premalignancies of the vulva, vagina, anus, and oropharynx. Results A total of 178,036 women were identified: 89,018 with a previous diagnosis of CIN3 and 89,018 matched control subjects without a history of CIN3. Women with a history of CIN3 showed increased risk of HPV-related carcinomas and premalignancies, with incidence rate ratios of 3.85 (95% CI, 2.32 to 6.37) for anal cancer, 6.68 (95% CI, 3.64 to 12.25) for anal intraepithelial neoplasia grade 3, 4.97 (95% CI, 3.26 to 7.57) for vulvar cancer, 13.66 (93% CI, 9.69 to 19.25) for vulvar intraepithelial neoplasia grade 3, 86.08 (95% CI, 11.98 to 618.08) for vaginal cancer, 25.65 (95% CI, 10.50 to 62.69) for vaginal intraepithelial neoplasia grade 3, and 5.51 (95% CI, 1.22 to 24.84) for oropharyngeal cancer. This risk remained significantly increased, even after long-term follow-up of up to 20 years. Conclusion This population-based study shows a long-lasting increased risk for HPV-related carcinomas and premalignancies of the anogenital and oropharyngeal region after a CIN3 diagnosis. Studies that investigate methods to prevent this increased risk in this group of patients, such as intensified screening or vaccination, are warranted.
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http://dx.doi.org/10.1200/JCO.2016.71.4543DOI Listing
August 2017

Multimodal Hyperspectroscopic Imaging for Detection of High-Grade Cervical Intraepithelial Neoplasia.

J Low Genit Tract Dis 2017 Jul;21(3):166-170

1Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, the Netherlands; 2Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands; and 3Department of Obstetrics and Gynaecology, Catharina Hospital Eindhoven, Eindhoven, the Netherlands.

Objective: Numerous new alternative digital colposcopy techniques have been developed, of which multimodal hyperspectroscopy (MHS) showed a high sensitivity in previous studies. The objective of this prospective single-center cohort study was to evaluate the clinical value of MHS for detecting high-grade cervical intraepithelial neoplasia in a colposcopy referral population and colposcopy follow-up population, to assess whether MHS could be safely used to improve care for women at risk for high-grade cervical intraepithelial neoplasia.

Materials And Methods: A total of 125 women from a colposcopy referral population and colposcopy follow-up population were evaluated with MHS and tested for the presence of high-risk human papillomavirus (HPV) with HPV-16/18 genotyping. Spectroscopic measurements of the cervix were taken and compared with an end point based on histology, high-risk HPV, and cytology. Evaluable data for analysis were collected from 102 of the subjects. Sensitivity, specificity, and predictive values were calculated for MHS and colposcopic impression based on conventional colposcopic examination.

Results: From the total study population of the 102 patients, 47 were enrolled in the colposcopy referral group and 55 in the colposcopy follow-up group. The MHS yielded a sensitivity of 93.6% (95% CI = 78.6-99.2), with a corresponding specificity of 42.3% (95% CI = 30.6-54.6) in the group with a composite end point. No adverse effects occurred, and patient acceptability was high.

Conclusions: Multimodal hyperspectroscopy is a digital colposcopy technique that offers an easy, rapid, well-tolerated point-of-care assessment with a high sensitivity for the presence of high-grade cervical intraepithelial lesions, however, with a low specificity, resulting in limited clinical value.
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http://dx.doi.org/10.1097/LGT.0000000000000309DOI Listing
July 2017

Measuring health-related quality of life in cervical cancer patients: a systematic review of the most used questionnaires and their validity.

BMC Med Res Methodol 2017 01 26;17(1):15. Epub 2017 Jan 26.

Department of Operating Rooms, Radboud University Medical Centre, Radboudumc Institute for Health Sciences, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Background: Data on health-related quality of life (HRQoL) is paramount for shared and evidence based decision-making. Since an overview of cervical cancer HRQoL tools and their validity appears to be lacking, we performed a systematic review on usage of disease specific HRQoL instruments in cervical cancer patients and their psychometric properties to identify the most suitable cervical cancer specific HRQoL tool.

Methods: We searched Pubmed, EMBASE and PsycINFO from inception up to 18 October 2016 for studies on quality of life in cervical cancer patients. Data extraction and HRQoL identification was performed by two independent reviewers. Validation studies of the identified cervical cancer specific HRQoL tools were retrieved and assessed on psychometric properties using the COSMIN checklist. All used cervical cancer specific HRQoL instruments were scored and ranked according to their psychometric properties.

Results: We included 156 studies (20,690 patients) and identified 31 HRQoL tools. The EORTC QLQ-CX24 (35 studies; 5,556 patients) and FACT-Cx (22 studies; 4,224 patients) were the only cervical cancer specific tools. The EORTC QLQ-CX24 had 4 out of 9 positive rated psychometric properties; internal consistency, content and construct validity, and agreement. Criterion validity, reliability, and interpretability scored doubtful. Responsiveness and floor- and ceiling effects were not reported. The FACT-Cx had 2 out of 9 positive rated psychometric properties; internal consistency and agreement. Content validity, reliability, and interpretability scored doubtful while criterion and construct validity scored negative. Responsiveness and floor- and ceiling effects were not reported.

Conclusion: The validity of the often used EORTC QLQ-CX24 questionnaire for cervical cancer patients remains uncertain as 5 out of 9 psychometric properties were doubtful or not reported in current literature. Cervical cancer specific HRQoL tools should therefore always be used in conjunction with validated generic cancer HRQoL tools until proper validity has been proven, or a more valid tool has been developed.
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http://dx.doi.org/10.1186/s12874-016-0289-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5270308PMC
January 2017

Clinically applied procedures for human ovarian tissue cryopreservation result in different levels of efficacy and efficiency.

J Assist Reprod Genet 2016 Dec 6;33(12):1605-1614. Epub 2016 Oct 6.

Department of Obstetrics and Gynecology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.

Purpose: Different protocols are being used worldwide for the cryopreservation of human ovarian tissue for fertility preservation purposes. The efficiency and efficacy of the majority of these protocols has not been extensively evaluated, possibly resulting in sub-optimally cryopreserved ovarian tissue. To address the impact of this issue, we assessed the effects of two clinically successful human ovarian tissue slow-freezing cryopreservation procedures on the quality of the cryopreserved tissue.

Methods: To differentiate between cryopreservation () versus thawing () related effects, four combinations of these two (A and B) very different cryopreservation/thawing protocols (AA, AB, BA, BB) were studied. Before and after cryopreservation and thawing, the percentage of living and morphologically normal follicles, as well as the overall tissue viability, was assessed.

Results: Our experiments revealed that the choice of the cryopreservation protocol noticeably affected the overall tissue viability and percentage of living follicles, with a higher viability after protocol B when compared to A. No statistically significant differences in tissue viability were observed between the two thawing protocols, but thawing protocol B required considerably more human effort and materials than thawing protocol A. Tissue morphology was best retained using the BA combination.

Conclusion: Our results indicate that extensive and systematical evaluation of clinically used protocols is warranted.
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http://dx.doi.org/10.1007/s10815-016-0816-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5171896PMC
December 2016

Vaginal Radical Trachelectomy for Early-Stage Cervical Cancer: Increased Recurrence Risk for Adenocarcinoma.

Int J Gynecol Cancer 2016 09;26(7):1293-9

*Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, the Netherlands; †Department of Gynecological Oncology, UMC Utrecht C9ncer Center, Utrecht, the Netherlands.

Objective: To evaluate consecutive vaginal radical trachelectomies (VRTs) in early-stage cervical cancer in the 2 main referral centers for fertility-preserving surgery in the Netherlands.

Materials And Methods: Oncology, fertility, and obstetrical data were recorded in a regional database of all VRTs without neoadjuvant chemotherapy performed in 2 major referral centers between 2000 and 2015.

Results: Most of the patients (91.7%) had stage IB1 disease. In 72.0%, squamous cell carcinoma was the histologic diagnosis; in 24.2%, adenocarcinoma; and in 3.8%, adenosquamous carcinoma. The median follow-up was 51 months.Nine (6.8%) recurrences occurred, 4 resulting in death of disease (death rate, 3.0%). Recurrence rates were 12.5% for adenocarcinoma, 20% for adenosquamous carcinoma, and 4.2% for squamous cell carcinoma (P < 0.01).From 117 women, data about fertility and obstetrical outcome were obtained. Almost 60% of women attempted to conceive after a VRT. Of these women, 40% needed fertility treatment. A total of 47 pregnancies were established, and a total of 37 children were born of which 30 (81.1%) were delivered after 32 weeks of gestational age.

Conclusions: Nonsquamous cell histology and high-grade disease are associated with a significantly higher risk of recurrence in the univariate and multivariate analyses. Women with both these histology features should be counseled reticently for VRT.Pregnancies after VRT must be regarded as high-risk pregnancies with a high prematurity rate.
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http://dx.doi.org/10.1097/IGC.0000000000000763DOI Listing
September 2016