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Contains fulltext : 294530.pdf (Publisher’s version ) (Open Access) OBJECTIVE: An emergency (rescue) cervical cerclage can be offered to pregnant women presenting with dilatation and prolapsed membranes in the second trimester of pregnancy because of cervical insufficiency. This study aimed to investigate the effectiveness of an emergency cerclage in both singleton and twin pregnancies in the prevention of extreme premature birth. DATA SOURCES: We performed a systematic literature search in PubMed and Embase from inception to June 2022 for transvaginal cervical emergency cerclages. STUDY ELIGIBILITY CRITERIA: All studies on transvaginal cervical emergency cerclages with at least 5 patients and reporting survival were included. METHODS: Included studies were assessed for quality and risk of bias with an adjusted Quality In Prognosis Studies tool. Random-effects meta-analyses and meta-regressions were performed for the primary outcome: survival. RESULTS: Our search yielded 96 studies, incorporating 3239 women, including 14 studies with an expectant management control group, incorporating 746 women. Overall survival after cervical emergency cerclage was 74%, with a fetal survival of 88% and neonatal survival of 90%. Singleton and twin pregnancies showed similar survival, with a pregnancy prolongation of 52 and 37 days and a gestational age at delivery of 30 and 28 weeks, respectively. Meta-regression analyses indicated a significant inverse association between mean gestational age at diagnosis and pregnancy prolongation and no association between dilatation or gestational age at diagnosis and gestational age at delivery. Compared with expectant management, emergency cerclage significantly increased overall survival by 43%, fetal survival by 17% and neonatal survival by 22%, along with a significant pregnancy prolongation of 37 days and reduction in delivery at

Contains fulltext : 288072.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Immunostaining with p16(INK4a) (p16), a tumor-suppressor surrogate protein biomarker for high-risk human papillomavirus (hrHPV) oncogenic activity, may complement standard hematoxylin and eosin (H&E) histology review, and provide more objective criteria to support the cervical intraepithelial neoplasia (CIN) diagnosis. With this study we assessed the impact of p16 immunohistochemistry on CIN grading in an hrHPV-based screening setting. MATERIAL AND METHODS: In this post-hoc analysis, 326 histology follow-up samples from a group of hrHPV-positive women were stained with p16 immunohistochemistry. All H&E samples were centrally revised. The pathologists reported their level of confidence in classifying the CIN lesion. RESULTS: Combining H&E and p16 staining resulted in a change of diagnosis in 27.3% (n = 89) of cases compared with the revised H&E samples, with a decrease of 34.5% (n = 18) in CIN1 and 22.7% (n = 15) in CIN2 classifications, and an increase of 18.3% (n = 19) in no CIN and 20.7% (n = 19) in CIN3 diagnoses. The level of confidence in CIN grading by the pathologist increased with adjunctive use of p16 immunohistochemistry to standard H&E. CONCLUSIONS: This study shows that adjunctive use of p16 immunohistochemistry to H&E morphology reduces the number of CIN1 and CIN2 classifications with a proportional increase in no CIN and CIN3 diagnoses, compared with standard H&E-based CIN diagnosis alone. The pathologists felt more confident in classifying the material with H&E and p16 immunohistochemistry than by using H&E alone, particularly during assessment of small biopsies. Adjunctive use of p16 immunohistochemistry to standard H&E assessment of CIN would be valuable for the diagnostic accuracy, thereby optimizing CIN management and possibly decreasing overtreatment.

Contains fulltext : 177357.pdf (Publisher’s version ) (Open Access) In 2017 the cervical cancer screening program in The Netherlands will be revised. Cervical smears will primarily be tested for the presence of high-risk human papillomavirus (hrHPV) instead of cytology, and vaginal self-sampling will be offered to non-responders. This includes a potential risk that part of the women who would otherwise opt for a cervical smear will wait for self-sampling. However, self-sampling for hrHPV in a responder population has never been studied yet. The aim of this study was to investigate the applicability and accuracy of self-sampling in detecting hrHPV in a screening responder population. A total of 2049 women, aged 30-60years, participating in the screening program in The Netherlands were included from April 2013 to May 2015. After they had their cervical smear taken, women self-collected a cervicovaginal sample with a brush-based device, the Evalyn Brush. Both the cervical smear and self-sample specimen were tested with the COBAS 4800 HPV platform. The hrHPV prevalence was 8.0% (95% CI 6.9-9.2) among the physician-taken samples, and 10.0% (95% CI 8.7-11.3) among the self-samples. There was 96.8% (95% CI 96.0-97.5) concordance of hrHPV prevalence between self-samples and physician-taken samples. Women in our study evaluated self-sampling as convenient (97.1%), user-friendly (98.5%), and 62.8% preferred self-sampling over a physician-taken sampling for the next screening round. In conclusion, self-sampling showed high concordance with physician-taken sampling for hrHPV detection in a responder screening population and highly acceptable to women. Implementation of HPV-self-sampling for the responder population as a primary screening tool may be considered.

Contains fulltext : 174739.pdf (Publisher’s version ) (Closed access) The aim of this study was to evaluate the clinical utility of p16/Ki-67 dual staining, for the identification of CIN in high-risk HPV-positive women from a non-responder screening cohort. P16/Ki-67 dual staining, Pap cytology, and HPV16/18 genotyping were performed on physician-taken liquid-based samples from 495 women who tested high-risk HPV positive on self-sampled material (PROHTECT-3B study). Different triage strategies involving p16/Ki-67 dual staining were evaluated for sensitivity, specificity, and predictive value for >/=CIN2 and >/=CIN3, and compared to Pap cytology with a threshold of atypical cells of undetermined significance. Centrally revised histology or an adjusted endpoint with combined high-risk HPV negative and cytology negative follow-up at 6 months was used as gold standard. Pap cytology (threshold atypical cells of undetermined significance) triage of high-risk HPV-positive samples showed a sensitivity of 93% (95% confidence interval: 85-98) with a specificity of 49% (95% confidence interval: 41-56) for >/=CIN3. Three triage strategies with p16/Ki-67 showed a significantly increased specificity with similar sensitivity. P16/Ki-67 triage of all high-risk HPV-positive samples had a sensitivity of 92% (95% confidence interval: 84-97) and a specificity of 61% (95% confidence interval: 54-69) for >/=CIN3. Applying p16/Ki-67 triage to only high-risk HPV-positive women with low-grade Pap cytology showed a similar sensitivity of 92% (95% confidence interval: 84-97), with a specificity for >/=CIN3 of 64% (95% confidence interval: 56-71). For high-risk HPV-positive women with low-grade and normal Pap cytology, triage with p16/Ki-67 showed a sensitivity of 96% (95% confidence interval: 89-99), and a specificity of 58% (95% confidence interval: 50-65). HPV16/18 genotyping combined with Pap cytology showed a sensitivity and specificity for >/=CIN3 similar to Pap cytology with an atypical cells of undetermined significance threshold. Because the quality of Pap cytology worldwide varies, and differences in sensitivity and specificity are limited between the three selected strategies, p16/Ki-67 triage of all high-risk HPV-positive samples would be the most reliable strategy in triage of high-risk HPV-positive women with an increased specificity and similar sensitivity compared with Pap cytology triage.

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.

Contains fulltext : 182397.pdf (Publisher’s version ) (Open Access) 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.

Contains fulltext : 137734.pdf (Publisher’s version ) (Closed access) BACKGROUND: Primary high-risk human papillomavirus (hrHPV) testing in cervical cancer screening shows relatively low specificity, which makes triage testing necessary. In this study, DNA methylation analysis was compared with cytology for triage testing in hrHPV-positive women. Moreover, feasibility of DNA methylation analysis directly on brush-based self-sampled specimens was assessed. METHODS: Non-responding women from population-based screening were invited to self-collect a cervico-vaginal specimen for hrHPV testing; hrHPV-positive women were referred to a physician for triage liquid-based cytology. DNA methylation analysis was performed on 128 hrHPV-positive physician-collected triage samples and 50 matched brush self-samples with QMSP for C13ORF18, EPB41L3, JAM3 and TERT. RESULTS: In physician-taken triage material, DNA methylation analysis of JAM3 showed the highest combined specificity (88%) and sensitivity (82%) for detection of CIN3+, whereas cytology showed a specificity of 48% and a sensitivity of 91%. Out of 39 women with abnormal cytology and normal histology (false-positive by cytology), 87% were negative for JAM3 and 90% for C13ORF18 methylation. Agreement between DNA methylation analysis performed directly on the matched self-sampled material and physician-taken samples was 88% for JAM3 (kappa=0.75, P

Contains fulltext : 139172.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Methylation marker analysis using bi-marker panel MAL/miR-124-2 is a promising triage test for identifying cervical (pre)cancer in high-risk human papillomavirus (hrHPV) positive women. Bi-marker panel MAL/miR-124-2 can be applied directly on self-sampled cervico-vaginal material and its sensitivity is non-inferior to that of cytology, yet at the cost of more colposcopy referrals. Our objective was to increase specificity of MAL/miR-124-2 methylation analysis by varying the assay thresholds and adding HPV16/18 genotyping. METHODS: 1019 hrHPV-positive women were selected from a randomized controlled self-sampling trial (PROHTECT-3; 33-63 years, n=46,001) and nine triage strategies with methylation testing of MAL/miR-124-2 and HPV16/18 genotyping were evaluated. The methylation assay threshold was set at four different predefined levels which correspond with clinical specificities for end-point cervical intra-epithelial grade 3 or worse (CIN3+) of 50%, 60%, 70%, and 80%. RESULTS: The CIN3+ sensitivity of methylation analysis decreased (73.5 to 44.9%) while specificity increased (47.2 to 83.4%) when increasing the assay threshold. CIN3+ sensitivity and specificity of HPV16/18 genotyping were 68.0% and 65.6%, respectively. Combined methylation analysis at threshold-80 and HPV16/18 genotyping yielded similar CIN3+ sensitivity as that of methylation only at threshold-50 (77.6%) with an increased specificity (54.8%). CONCLUSIONS: Combined triage by MAL/miR-124-2 methylation analysis with threshold-80 and HPV16/18 genotyping reaches high CIN3+ sensitivity with increased specificity to identify women with cervical (pre)cancer among HPV self-sample positive women. The combined strategy is attractive as it is fully molecular and identifies women at the highest risk of cervical (pre)cancer because of strongly elevated methylation levels and/or HPV16/18 positivity.

Contains fulltext : 125819.pdf (Publisher’s version ) (Closed access) Abstract Objective: To determine the reasons for women's anxiety and psychological stress before and during colposcopy, in order to define strategies to decrease their stress. Methods: Qualitative study with 15 women participating in four focus groups between April 2011 and April 2012. All participants were diagnosed with a cervical cytological abnormality and attended a gynecologist's clinic to undergo colposcopy. The focus group interview was audio-taped and transcribed verbatim. The data were analyzed using qualitative content analysis to identify themes. Results: Psychological stress before colposcopy was seen as being caused by unsatisfactory explanation of abnormal cervical smears and the colposcopy procedure itself. Additionally, a fear of cancer, pain and discomfort, embarrassment, waiting time in the hospital, and a longer interval between referral and the actual colposcopy appointment increased psychological stress and anxiety. Women indicated that more detailed and practical information about the cervical smear result and the colposcopy procedure may reduce stress and anxiety. Conclusion: In order to minimize the adverse psychological consequences of an abnormal cervical smear and colposcopy, timely, practical and detailed information needs to be provided to the women, and waiting and access times need to be as short as possible. These measures may reduce the psychological stress and anxiety, however some stress and anxiety will always remain, and may even be desirable in order to ensure proper follow-up of abnormal cervical smears.

Contains fulltext : 171859.pdf (Publisher’s version ) (Open Access) INTRODUCTION: High-risk human papillomavirus (hrHPV) testing is expected to replace cytology as primary screening method for cervical cancer screening in an increasing number of countries. The high sensitivity of hrHPV testing is combined with a limited specificity which makes triaging of hrHPV positive women necessary. As an ideal triage method does not yet exist, an optimal triage strategy for hrHPV positive women based on current knowledge should be obtained. The aim of this article is to present an overview of available options for triage of hrHPV positive women, with their strengths and limitations and possible future opportunities. AREAS COVERED: Current knowledge on morphological biomarkers, molecular biomarkers and combined triage strategies will be discussed to give an overview of the state-of-the-art on triaging hrHPV positive women. The literature search was limited to studies on triage strategies for hrHPV positive women. Expert commentary: Experience with morphology-based biomarkers makes these a valuable triage method. However, they lack the ability of differentiating productive from transforming infections. Molecular biomarkers are objective, highly reproducible, can be used in high throughput testing, and show promising results. With more extensive knowledge on these molecular markers, cervical cancer screening may transform to a full molecular screening in the future.

Objectives DNA methylation analysis of cancer-related genes is a promising tool for HPV-positive women to identify those with cervical (pre)cancer (CIN3+) in need of treatment. However, clinical performance of methylation markers can be influenced by the sample type utilized. We describe a multiplex quantitative methylation-specific PCR that targets FAM19A4 and mir124-2 loci, to detect CIN3+ using both HPV-positive lavage- and brush self-samples. Methods We determined methylation thresholds for clinical classification using HPV-positive training sets comprising lavage self-samples of 182 women (including 40 with CIN3+) and brush self-samples of 224 women (including 61 with CIN3+). Subsequently, independent HPV-positive validation sets of 389 lavage self-samples (including 78 with CIN3+), and 254 brush self-samples (including 72 with CIN3+) were tested using the preset thresholds. Furthermore, the clinical performance of combined methylation analysis and HPV16/18 genotyping was determined. Results Training set analysis revealed similar FAM19A4 and mir124-2 thresholds for both self-sample types to yield highest CIN3+ sensitivity at 70% specificity. Validation set analysis resulted in a CIN3+ sensitivity of 70.5% (95%CI: 60.4–80.6) at a specificity of 67.8% (95%CI: 62.7–73.0) for lavage self-samples, and a CIN3+ sensitivity of 69.4% (95%CI: 58.8–80.1) at a 76.4% (95%CI: 70.2–82.6) specificity for brush self-samples. In combination with HPV16/18 genotyping, CIN3+ sensitivity and specificity were 88.5% (95%CI: 81.4–95.6) and 46.0% (95%CI: 40.4–51.5) for lavage self-samples, and 84.7% (95%CI: 76.4–93.0) and 54.9% (95%CI: 47.7–62.2) for brush self-samples. Conclusions FAM19A4/mir124-2 methylation analysis performs equally well in HPV-positive lavage- and brush self-samples to identify women with CIN3+. In combination with HPV16/18 genotyping, significantly higher CIN3+ sensitivities are obtained, at decreased specificity., Highlights • FAM19A4/mir124-2 triage of HPV-positive self-samples is a feasible and promising tool • FAM19A4/mir124-2 analysis identifies HPV-positive women at risk of cervical cancer. • FAM19A4/mir124-2 analysis performs equally well in lavage and brush self-samples. • Further validation of HPV self-sampling with FAM19A4/mir124-2 triage is warranted

Primary screening using high-risk human papillomavirus (hrHPV) detection has been suggested as a way of improving cervical cancer prevention. Women currently not attending screening (nonresponders) are more likely to participate when given the opportunity of self-sampling for hrHPV testing. The Evalyn Brush is a new cervicovaginal self-sampling device, developed specifically to meet women's demands, which is user-friendly and easy to use. The aims of this study were to investigate agreement of hrHPV detection by two PCR methods between the Evalyn Brush and physician-obtained samples and to study women's acceptance of this self-sampling device. Each of 134 women visiting the gynecology outpatient clinic collected a self-obtained sample (self-sample) and completed a questionnaire. The brush was stored dry. After self-sampling, a trained physician obtained a conventional cervical cytology specimen in ThinPrep medium. HrHPV detection was performed using the SPF 10 -DEIA-LiPA 25 and GP5+/6+-LQ-test. The overall agreement for hrHPV detection using SPF 10 -DEIA-LiPA 25 between the self-sample and the physician-taken sample was 85.8% (kappa value, 0.715; 95% confidence interval [CI], 0.597 to 0.843; P = 1.000). The overall agreement for hrHPV detection using GP5+/6+-LQ between the self-sample and the physician-taken sample was 86.6% (kappa value, 0.725; 95% CI, 0.607 to 0.843; P = 0.815). Ninety-eight percent of the women rated their experience as good to excellent. Moreover, 95% of women preferred self-sampling to physician sampling. Self-sampling using the dry Evalyn Brush system is as good as a physician-taken sample for hrHPV detection and is highly acceptable to women. To validate this self-sampling device for clinical use, a large screening cohort should be studied.

BACKGROUND: The Nuss procedure was introduced at our center in 1999. The operation was mainly performed for cosmesis. Little information is available regarding the influence of this operation on lung function. METHODS: The aim of this study, a prospective analysis, was to analyze the effect of the Nuss procedure on lung function variables. Between 1999 and 2007 a total of 203 patients with pectus excavatum were treated with the Nuss procedure, of whom 145 (104 male, 41 female) were located at Emma Children's Hospital. In the latter subset of consecutive patients, static lung function variables [total lung capacity (TLC), functional residual capacity (FRC), vital capacity (VC)] and dynamic lung function variables [forced expired volume in 1 s (FEV(1)), maximum expiratory flow (MEF(50))] were performed using spirometry and body box measurements at four time points: prior to operation (T0), 6 months after the Nuss procedure (T1, n = 111), prior to removal of the Nuss bar (T2, n = 74), and 6 months after removal (T3, n = 53). All values were expressed as a percent of normal values for sex, age, and height. Results were compared with a paired-samples t-test, with the level of significance at p = 0.05. RESULTS: At 6 months after bar insertion the TLC, FRC, VC, FEV(1), and MEF(50) showed a significant increase; and prior to bar removal the FRC and MEF(50) showed significantly increased values. At 6 months after Nuss bar removal, none of the lung function variables showed any significant change compared to the preoperative values. CONCLUSION: After the Nuss procedure for pectus excavatum, there was no improvement of pulmonary function, but neither was the patient's pulmonary function harmed by resolving a largely cosmetic problem

Cytology alone, or combined with HPV16/18 genotyping, might be an acceptable method for triage in hrHPV-cervical cancer screening. Previously studied HPV-genotype based triage algorithms are based on cytology performed without knowledge of hrHPV status. The aim of this study was to explore the value of hrHPV genotyping combined with cytology as triage tool for hrHPV-positive women. 520 hrHPV-positive women were included from a randomised controlled self-sampling trial on screening non-attendees (PROHTECT-3B). Eighteen baseline triage strategies were evaluated for cytology and hrHPV genotyping (Roche Cobas 4800) on physician-sampled triage material. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), referral rate, and number of referrals needed to diagnose (NRND) were calculated for CIN2+ and CIN3+. A triage strategy was considered acceptable if the NPV for CIN3+ was ≥98%, combined with maintenance or improvement of sensitivity and an increase in specificity in reference to the comparator, being cytology with a threshold of atypical cells of undetermined significance (ASC-US). Three triage strategies met the criteria: HPV16+ and/or ≥LSIL; HPV16+ and/or ≥HSIL; (HPV16+ and/or HPV18+) and/or ≥HSIL. Combining HPV16+ and/or ≥HSIL yielded the highest specificity (74.9%, 95% CI 70.5-78.9), with a sensitivity (94.4%, 95% CI 89.0-97.7) similar to the comparator (93.5%, 95% CI 87.7-97.1), and a decrease in referral rate from 52.2% to 39.5%. In case of prior knowledge of hrHPV presence, triage by cytology testing can be improved by adjusting its threshold, and combining it with HPV16/18 genotyping. These strategies improve the referral rate and specificity for detecting CIN3+ lesions, while maintaining adequate sensitivity.

Contains fulltext : 152209.pdf (Publisher’s version ) (Closed access) BACKGROUND: Studies of see-and-treat management of cervical intraepithelial neoplasia (CIN) vary in their inclusion criteria, resulting in a broad range of overtreatment rates. OBJECTIVES: To determine overtreatment rates in see-and-treat management of women referred for colposcopy because of suspected CIN, in order to define circumstances supporting see-and-treat management. SEARCH STRATEGY: MEDLINE, EMBASE, and the Cochrane Library were searched from inception up to 12 May 2014. SELECTION CRITERIA: Studies of see-and-treat management in women with a reported cervical smear result, colposcopic impression, and histology result were included. DATA COLLECTION AND ANALYSIS: Methodological quality was assessed with the Newcastle-Ottawa scale. We used the inverse variance method for pooling incidences, and a random-effects model was used to account for heterogeneity between studies. Overtreatment was defined as treatment in patients with no CIN or CIN1. MAIN RESULTS: Thirteen studies (n = 4611) were included. The overall overtreatment rate in women with a high-grade cervical smear and a high-grade colposcopic impression was 11.6% (95% CI 7.8-15.3%). The overtreatment rate in women with a high-grade cervical smear and low-grade colposcopic impression was 29.3% (95% CI 16.7-41.9%), and in the case of a low-grade smear and high-grade colposcopic impression it was 46.4% (95% CI 15.7-77.1%). In women with a low-grade smear and low-grade colposcopic impression, the overtreatment rate was 72.9% (95% CI 68.1-77.7%). AUTHOR'S CONCLUSIONS: The pooled overtreatment rate in women with a high-grade smear and high-grade colposcopic impression is at least comparable with the two-step procedure, which supports the use of see-and-treat management in this subgroup of women. TWEETABLE ABSTRACT: See-and-treat management is justified in the case of a high-grade smear and a high-grade colposcopic impression.

Contains fulltext : 155303.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Triage of HPV screen-positive women is needed to identify those with underlying cervical intraepithelial neoplasia grade 2/3 or worse (CIN2/3+). Presently, cytology on a physician-taken cervical scrape is mostly accepted as triage test, but needs follow-up testing in order not to miss severe disease. Here, we evaluated the performance of combined cytology and bi-marker CADM1/MAL-methylation analysis as triage test on physician-taken cervical scrapes of HPV positive women. METHODS: In this post-hoc analysis, we used 364 left-over HPV positive cytology triage samples of participants of a randomized controlled trial (PROHTECT-3: n=46,001) performed in population-based cervical screening. Study endpoints were CIN2+ and CIN3+ detection. Cytology testing with and without methylation marker analysis was evaluated with regard to sensitivity, specificity, positive and negative predictive value, and referral rate. RESULTS: Bi-marker CADM1/MAL-methylation positivity increased proportionally with severity of underlying lesions. Overall, cytology and bi-marker CADM1/MAL-methylation analysis yielded similar performances with regard to CIN3+ detection, yet in combination a significantly higher sensitivity for CIN3+ (88.7%) was obtained at a specificity of 53.6% and a colposcopy referral rate of 53.6%. The combined strategy detected all six cervical cancers, whereas triage by cytology alone failed to detect two of them. CONCLUSIONS: Cytology and bi-marker CADM1/MAL-methylation analysis perform complementary for CIN2+/CIN3+ detection when used as triage tool on cervical scrapes of HPV positive women. This approach not only results in a higher CIN3+ sensitivity than cytology triage with an acceptable referral rate, but also seems to reduce the risk of missing cervical cancers and advanced high-grade lesions.

INTRODUCTION: The aim of the study was to compare results of the Nuss procedure in adults and children. METHODS: The data were collected prospectively. Antibiotic prophylaxis was used in all patients. Differences were tested statistically. RESULTS: A total of 35 adults (28 men; male/female ratio 4:1) with a median age of 23 years (range 18 years to 47 years 1 month) were included in the study. A previous Welch operation had been performed in one (3%). The median operating time was 65 minutes (range 45-105 minutes). Two bars were inserted in one patient, and stabilizers were used in all. Pneumothorax occurred in 9 (26%), wound abscess in 3 (9%), and bar slips in 5 (14%). The median hospital stay was 7 days (range 4-10 days). Bars were removed in 14 (40%) patients without complications. Follow-up occurred 6 and 12 months after bar removed, at which times no recurrence of the pectus and no sternal protrusions were seen. In the other part of the study, 141 children and adolescents (105 boys; male/female ratio 3:1) with a median age of 13 years (range 4 years 11 months to 17 years 8 months) were included. A previous Welch operation had been performed in five (4%). Two bars were inserted in four, and stabilizers were used in 100 (71%). The median operating time was 65 minutes (40-185 minutes). Pneumothorax occurred in 33 (24%), wound abscess in 1 (0.7%), and bar slips in 18 (13%). The median hospital stay was 7 days (range 5-18 days). Bars were removed in 77 (55%) without complications. Follow-up occurred 6 and 12 months after bar removed, and the last follow-up was eventually planned at the end of growth (age 18). The pectus recurred in one patient with Marfan syndrome, and sternal protrusion occurred in one. Differences between groups were as follows: a significantly higher proportion of adult patients were treated with stabilizers (P < 0.001), and there were significantly more wound abscesses in adults (P < 0.001). CONCLUSIONS: The Nuss procedure is as effective for correcting pectus excavatum in adults as it is in children. However, in adults the bars tended to be less stable, and wound abscesses occurred more frequently

We determined whether the participation rate for a brush-based cervicovaginal self-sampling device is noninferior to the participation rate for a lavage-based one for testing for hrHPV (high-risk human papillomavirus). Additionally, positivity rates for hrHPV, the detection rates for cervical intraepithelial neoplasia grades 2 and 3 or worse (CIN2+/3+), and user comfort were compared. A total of 35,477 non-responders of the regular cervical screening program aged 33-63 years were invited to participate. Eligible women (n = 30,130) were randomly assigned to receive either a brush-based or a lavage-based device, and a questionnaire for reporting user convenience. Self-sampling responders testing hrHPV-positive were invited for a physician-taken sample for cytology; triage-positive women were referred for colposcopy. A total of 5,218 women participated in the brush-based sampling group (34.6%) and 4809 women in the lavage-based group (31.9%), i.e. an absolute difference of 2.7% (95%CI 1.8-4.2). The hrHPV-positivity rates in the two groups were identical (8.3%, relative risk (RR) 0.99, 95%CI 0.87-1.13). The detection of CIN2+ and CIN3+ in the brush group (2.0% for CIN2+; 1.3% for CIN3+) was similar to that in the lavage group (1.9% for CIN2+; 1.0% for CIN3+) with a cumulative RR of 1.01, 95%CI 0.83-1.24 for CIN2+ and 1.25, 95%CI 0.92-1.70 for CIN3+. The two self-sampling devices performed similarly in user comfort. In conclusion, offering a brush-based device to non-responders is noninferior to offering a lavage-based device in terms of participation. The two self-sampling methods are equally effective in detecting hrHPV, CIN2+/CIN3+ and are both well accepted.

We determined whether the participation rate for a brush-based cervicovaginal self-sampling device is noninferior to the participation rate for a lavage-based one for testing for hrHPV (high-risk human papillomavirus). Additionally, positivity rates for hrHPV, the detection rates for cervical intraepithelial neoplasia grades 2 and 3 or worse (CIN2+/3+), and user comfort were compared. A total of 35,477 non-responders of the regular cervical screening program aged 33-63 years were invited to participate. Eligible women (n = 30,130) were randomly assigned to receive either a brush-based or a lavage-based device, and a questionnaire for reporting user convenience. Self-sampling responders testing hrHPV-positive were invited for a physician-taken sample for cytology; triage-positive women were referred for colposcopy. A total of 5,218 women participated in the brush-based sampling group (34.6%) and 4809 women in the lavage-based group (31.9%), i.e. an absolute difference of 2.7% (95%CI 1.8-4.2). The hrHPV-positivity rates in the two groups were identical (8.3%, relative risk (RR) 0.99, 95%CI 0.87-1.13). The detection of CIN2+ and CIN3+ in the brush group (2.0% for CIN2+; 1.3% for CIN3+) was similar to that in the lavage group (1.9% for CIN2+; 1.0% for CIN3+) with a cumulative RR of 1.01, 95%CI 0.83-1.24 for CIN2+ and 1.25, 95%CI 0.92-1.70 for CIN3+. The two self-sampling devices performed similarly in user comfort. In conclusion, offering a brush-based device to non-responders is noninferior to offering a lavage-based device in terms of participation. The two self-sampling methods are equally effective in detecting hrHPV, CIN2+/CIN3+ and are both well accepted.

Contains fulltext : 136660.pdf (Publisher’s version ) (Closed access) OBJECTIVES: High attendance rates in cervical screening are essential for effective cancer prevention. Offering HPV self-sampling to non-responders increases participation rates. The objectives of this study were to determine why non-responders do not attend regular screening, and why they do or do not participate when offered a self-sampling device. METHODS: A questionnaire study was conducted in the Netherlands from October 2011 to December 2012. A total of 35,477 non-responders were invited to participate in an HPV self-sampling study; 5347 women did opt out. Finally, 30,130 women received a questionnaire and self-sampling device. RESULTS: The analysis was based on 9484 returned questionnaires (31.5%) with a self-sample specimen, and 682 (2.3%) without. Among women who returned both, the main reason for non-attendance to cervical screening was that they forgot to schedule an appointment (3068; 32.3%). The most important reason to use the self-sampling device was the opportunity to take a sample in their own time-setting (4763; 50.2%). A total of 30.9% of the women who did not use the self-sampling device preferred after all to have a cervical smear taken instead. CONCLUSIONS: Organisational barriers are the main reason for non-attendance in regular cervical screening. Important reasons for non-responders to the regular screening to use a self-sampling device are convenience and self-control.

Contains fulltext : 137129.pdf (Publisher’s version ) (Closed access) BACKGROUND: Cytology is a widely used method of triaging women who test positive for human papillomavirus (HPV). However, self-sampled specimens, which can substantially increase participation in screening programmes, are not suitable for accurate cytological assessment. We investigated whether direct DNA methylation-based molecular triage on self-sampled cervicovaginal specimens was non-inferior to cytology triage on additional physician-collected cervical samples in the detection of cervical intraepithelial neoplasia grade 2 (CIN2) or worse in women who did not attend cervical screening programmes. METHODS: In this randomised controlled non-inferiority trial, we invited women (aged 33-63 years) registered as non-attendees of cervical screening in the Netherlands in 2007 to submit a self-collected cervicovaginal sample for HPV testing. Using a computer-generated sequence, we randomly allocated women who tested positive for high-risk hrHPV on a self-sample to either triage by cytology on an additional physician-taken smear or direct triage on the self-sample by methylation analysis of MAL and miR-124-2 genes (1:1; stratified by age and region, with block sizes by age group). Triage-positive women in either group were referred for colposcopy. The primary endpoint was detection of CIN2 or worse, analysed by intention to treat. The non-inferiority margin was 0.80. This study is registered in the Primary Trial Register of the Netherlands, number NTR6026. FINDINGS: We invited 46 001 women to participate, 12 819 of whom returned self-sampled material; 1038 samples tested positive for high-risk HPV. Between Nov 1, 2010, and Dec 31, 2011, after exclusion of women who were ineligible, we enrolled and randomly allocated 515 women to methylation triage and 509 to cytology triage. The detection of CIN2 or worse with methylation triage was non-inferior to that with cytology triage (90 [17%] of 515 women vs 75 [15%] of 509 women; relative risk 1.19, 95% CI 0.90-1.57). Referral for colposcopy was more common in the molecular group (284 [55%] women) than in the cytology group (149 [29%] women; p

Contains fulltext : 87619.pdf (Publisher’s version ) (Closed access) Flaring of the costal arch may be part of the pectus excavatum deformity. This aspect will in rare cases be even worsen after the Nuss repair. This remaining deformity can be treated with a minimal subperichondral partial resection of the costal arch cartilage. In 5 patients, this additional technique regained good to excellent results. 01 september 2010

Cervical screening programs for detecting cancer and precancer have dramatically reduced the incidence and mortality rates of cervical cancer since the 1960s. The efficacy of the screening programs depends on participation and the accuracy of the screening tests. Unfortunately, the participation rates are suboptimal; more than half the women with cervical cancer have not or have only sporadically been screened. Increasing participation is the best way of maximizing the program's benefit. Furthermore, cytology screening lacks high sensitivity for high-grade cervical intraepithelial neoplasia (≥CIN2). High-risk human papillomavirus (hrHPV) screening is more sensitive in the detection of cervical intraepithelial neoplasia than cytology screening, but less specific, so that additional triage testing is still mandatory. The aim of this article is to reflect on the efficacy of current cervical cancer screening and on promising future screening strategies with primary hrHPV testing and additional triage strategies for hrHPV-positive screening results.

Contains fulltext : 118480.pdf (Publisher’s version ) (Open Access) BACKGROUND: Attendance rates of cervical screening programs can be increased by offering HPV self-sampling to non-attendees. Acceptability, DNA yield, lavage volumes and choice of hrHPV test can influence effectiveness of the self-sampling procedures and could therefore play a role in recruiting non-attendees. To increase user-friendliness, a frequently used lavage sampler was modified. In this study, we compared this second generation lavage device with the first generation device within similar birth cohorts. METHODS: Within a large self-sampling cohort-study among non-responders of the Dutch cervical screening program, a subset of 2,644 women received a second generation self-sampling lavage device, while 11,977 women, matched for age and ZIP-code, received the first generation model. The second generation device was different in shape, color, lavage volume, and packaging, in comparison to its first generation model. The Cochran's test was used to compare both devices for hrHPV positivity rate and response rate. To correct for possible heterogeneity between age and ZIP codes in both groups the Breslow-Day test of homogeneity was used. A T-test was utilized to compare DNA yields of the obtained material in both groups. RESULTS: Median DNA yields were 90.4 mug/ml (95% CI 83.2-97.5) and 91.1 mug/ml (95% CI 77.8-104.4, p= 0.726) and hrHPV positivity rates were 8.2% and 6.9% (p= 0.419) per sample self-collected by the second - and the first generation of the device (p= 0.726), respectively. In addition, response rates were comparable for the two models (35.4% versus 34.4%, p= 0.654). CONCLUSIONS: Replacing the first generation self-sampling device by an ergonomically improved, second generation device resulted in equal DNA yields, comparable hrHPV positivity rates and similar response rates. Therefore, it can be concluded that the clinical performance of the first and second generation models are similar. Moreover, participation of non-attendees in cervical cancer screening is probably not predominantly determined by the type of self-collection device.

Contains fulltext : 144729.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To determine the overtreatment rate at colposcopy in women who underwent a see-and-treat protocol. METHODS: We identified 3,192 patients (mean age 36 years, standard deviation 8.7) who underwent a see-and-treat protocol in Radboud University Nijmegen Medical Center between January 1981 and December 2010. Overtreatment, defined as cervical intraepithelial neoplasia 1 or less at final histopathology analysis, was investigated in relation to the age of the women, time of referral, cervical smear result, colposcopic impression, and histopathology result. RESULTS: A total of 579 women (18.1%, 95% confidence interval [CI] 16.7-19.5) were overtreated. The lowest overtreatment rate (4.5%, 95% CI 3.5-5.5) was seen in women with both a high-grade cervical smear result and a high-grade colposcopic impression. Women aged younger than 40 years were less likely to be overtreated (13.1%, 95% CI 11.7-14.5) than women aged 40-49 years (24.2% 95% CI 21.2-27.4, number needed to harm nine) and aged 50 years and older (42.2%, 95% CI 36.5-47.7, number needed to harm three). CONCLUSIONS: The overtreatment rate is low for patients with both a high-grade smear result and a high-grade colposcopic impression, justifying a see-and-treat approach for these patients. In women with either a high-grade smear result or a high-grade impression on colposcopy, a see-and-treat approach may still be preferable but has higher overtreatment rates. Given the side effects of cervical surgery on pregnancy outcome, young women, in particular those who have either a low-grade smear result or low-grade impression on colposcopy, are better served by a two-step approach. In older women, a see-and-treat policy may be preferable.

Background: Primary hrHPV testing in cervical cancer screening shows relatively low specificity. To decrease the number of unnecessary referrals for colposcopy, triage testing is necessary. In this study, DNA methylation analysis was compared with routine cytology for triage testing in hrHPV positive women. Moreover, feasibility of DNA methylation analysis directly on original brush-based self-sampled specimens was assessed. Methods: Non-responding women from population-based screening were invited to self-collect a cervico-vaginal specimen for hrHPV testing; hrHPV positive women were referred to a physician for liquid-based sampling. For this pilot study, DNA methylation analysis was performed on 128 triage samples and on 50 matched Evalyn brush self-samples with QMSP for C13ORF18, EPB41L3, JAM3 and TERT. Results: In the physician-taken triage material, DNA methylation analysis of JAM3 showed the highest specificity (88%) combined with a high sensitivity (82%) for detection of CIN3+, whereas cytology showed a specificity of 48% and a sensitivity of 91%. Out of 39 women with abnormal cytology and normal histology (false positive by cytology), 87% were negative for JAM3 and 90% for C13ORF18 methylation. The agreement for DNA methylation analysis performed directly on the matched self-sampled material and the physician-taken samples was 90% for C13ORF18 (κ=0.77; p Conclusion: DNA methylation analysis as a triage test in hrHPV positive women outperformed cytology due to higher specificity without losing its sensitivity and is also feasible to be performed directly on Evalyn Brush self-samplers. This might result in more correct referrals to the gynecologist and eliminate the need for a new scraping taken by a medical professional thereby offering great logistic and financial advantages. This study was financed by the Dutch Cancer Society (RUG-NKB2009-4577). Citation Format: Aniek Boers, Remko P. Bosgraaf, Roland W. van Leeuwen, Ed Schuuring, Leon FAG Massuger, Johan Bulten, Willem JG Melchers, Ate GJ van der Zee, Ruud LM Bekkers, Bea Wisman. DNA methylation analysis in self-sampled material as a triage test in hrHPV positive women. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1360. doi:10.1158/1538-7445.AM2014-1360