The risk of vaginal, vulvar and anal precancer and cancer according to high-risk HPV status in cervical cytology samples.

High-risk human papillomavirus (hrHPV) is the cause of virtually all cervical cancers, most vaginal and anal cancers, and some vulvar cancer cases. With HPV testing becoming the primary screening method for cervical cancer, understanding the link between cervical hrHPV infection and the risk of other anogenital cancers is crucial. We assessed the risk of vulvar, vaginal and anal cancer and precancer (VIN2+, VaIN2+ and AIN2+) in a prospective cohort study including 455,349 women who underwent cervical hrHPV testing in Denmark from 2005 to 2020. We employed Cox proportional hazard models, adjusting for age, calendar year and HPV vaccination status, and estimated hazard ratios (HRs) and 95% confidence intervals (CI). We used the Aalen Johansen estimator to calculate the absolute risks of VIN2+, VaIN2+ and AIN2+. In total, 15% of the women were hrHPV positive at baseline. A positive cervical hrHPV test was associated with increased incidence of vulvar, vaginal and anal squamous cell carcinoma (SCC). Five-year risk estimates of VIN2+, VaIN2+ and AIN2+ among hrHPV-positive women (0.45%, 0.14% and 0.12%) were higher than among hrHPV-negative women (0.14%, 0.01% and 0.05%). Particularly high risk was observed among the hrHPV-positive women of the oldest age, with a history of anogenital precancer and those not HPV vaccinated. In conclusion, our study confirms the association between cervical hrHPV infection and non-cervical anogenital precancers and cancers. Currently, no established risk threshold or guidelines for follow-up. As HPV testing becomes the primary method for cervical cancer screening, future data will help define high-risk groups and acceptable risk thresholds.

Human papillomavirus genotypes and risk of persistence and progression in women undergoing active surveillance for cervical intraepithelial neoplasia grade 2.

BACKGROUND: In recent years, active surveillance has been introduced as an alternative to excisional treatment in younger women with cervical intraepithelial neoplasia grade 2 because regression rates are high and excisional treatment is associated with increased risk of preterm birth. However, early identification of women at increased risk of persistence/progression is important to ensure timely treatment. Evidence is limited on biomarkers that may be used to identify women at increased risk of persistence/progression. OBJECTIVE: This study aimed to describe human papillomavirus HPV type-specific persistence/progression in women undergoing active surveillance for cervical intraepithelial neoplasia grade 2. STUDY DESIGN: We conducted a historical cohort study of women aged 23 to 40 years diagnosed with cervical intraepithelial neoplasia grade 2 at Aarhus University Hospital from 2000 to 2010. Women were identified through the Danish Pathology Data Bank (DPDB) and were considered as undergoing active surveillance if they had a first record of a cervical biopsy within 2 years after index diagnosis and no loop electrosurgical excision procedure before this. Human papillomavirus genotyping was performed on archived tissue samples using the HPV SPF10-DEIA-LiPA25 system (DNA ELISA [enzyme-linked immunosorbent assay] HPV SPF10 kit and RHA HPV SPF10-LiPA25 kit). Persistence/progression was defined as having a record of cervical intraepithelial neoplasia grade ≥2 in the DPDB determined on the last and worst diagnosis on a biopsy or loop electrosurgical excision procedure specimen during follow-up. We estimated the relative risk (95% confidence interval) of persistence/progression using a modified Poisson model. RESULTS: A total of 455 women were included. Two-thirds were aged ≤30 years (73.8%) at index diagnosis, and nearly half had a high-grade index cytology (48.8%). Overall, 52.2% of all women had cervical intraepithelial neoplasia grade ≥2 during follow-up; 70.5% were human papillomavirus-16-positive and 29.5% were positive for other human papillomavirus types. Human papillomavirus-16 was associated with a significantly higher risk of persistence/progression (relative risk, 1.64; 95% confidence interval, 1.37-1.95) compared with non-human papillomavirus-16. The risk of persistence/progression was highest in human papillomavirus-16-positive women with a high-grade index cytology compared with human papillomavirus-16-positive women with a low-grade cytology (relative risk, 1.29; 95% confidence interval, 1.03-1.61), whereas no differences were observed across age groups. CONCLUSION: The highest risk of persistence/progression was observed among human papillomavirus-16-positive women, particularly those with associated high-grade cytology. These findings suggest that early excisional treatment should be considered in this group of women.

Morbidity following robot-assisted surgery in a gynecological oncology setting: A cohort study.

INTRODUCTION: The objective of the study was to provide a comprehensive description of perioperative morbidity associated with robot-assisted surgery (RAS) in a gynecological oncology setting in order to improve the preoperative counseling of women and support shared decision-making. MATERIAL AND METHODS: All women scheduled for intended RAS between January 2015 and December 2022 were prospectively included in an electronic morbidity database for the analyses of perioperative complications. RESULTS: In total, 2225 women were included. Sixty-four patients (2.9%) experienced an intraoperative complication. Intraoperative complications were associated with a higher rate of conversion to laparotomy (15.6% vs. 1.8%, p < 0.001), a higher rate of major postoperative morbidity (9.3% vs. 2.4%, p < 0.001), and a higher rate of reoperation (9.3% vs. 1.7%, p < 0.001), compared to cases without intraoperative complications. Thirty-day postoperative morbidity was evaluated according to the Memorial Sloan-Kettering Cancer Center Surgical Secondary Events Grading System. Grade 3-5 events were considered major. A total of 57 patients (2.6%) experienced a major event after surgery, postoperative rupture of the vaginal vault being the most common complication requiring surgical intervention. Conversion to laparotomy occurred in 49 cases (2.2%) and was associated with higher intraoperative blood loss (300 mL vs. 25 mL, p < 0.001), a higher rate of postoperative major events (20.4% vs. 2.2%, p < 0.001), and a higher rate of reoperation (11.8% vs. 1.6%, p < 0.001). CONCLUSIONS: Our study demonstrates low rates of major perioperative morbidity and conversion to laparotomy after RAS performed by trained high-volume surgeons in a gynecological oncology setting.

The Incidence of Cervical Intraepithelial Neoplasia or Cervical Cancer in Women Referred With Postcoital Bleeding.

OBJECTIVES: The incidence of cervical cancer among patients with postcoital bleeding (PCB) was the primary objective of this study. Furthermore, the proportion of cervical intraepithelial neoplasia requiring treatment and the correlation between PCB and the presence of high-risk human papillomavirus (HPV) was determined. Lastly, the study aimed to identify risk factors among the referred women. METHODS: A retrospective cohort study was conducted at a university hospital in Denmark between January 1, 2017 and December 31, 2019. Women referred with PCB were identified with the ICD diagnosis codes "DN930 Postcoital and contact bleeding" and "DN930B Contact bleeding." Demographic and paraclinical data were extracted from the journals and the supportive systems: Patoweb and the Danish Microbiology Database. RESULTS: A total of 789 women were included in this study, with only 0.25% ( n = 2) diagnosed with cervical cancer and 2.5% ( n = 20) diagnosed with cervical intraepithelial neoplasia II-III and adenocarcinoma in situ. Human papillomavirus testing was only conducted in a minority of cases, and a low incidence of high-risk human papilloma virus was detected in the 22 cases, n = 5. CONCLUSIONS: A very low incidence of cervical cancer and high-grade cervical intraepithelial neoplasia reported among women referred with PCB. Prognostic factors as body mass index, smoking, and HPV vaccination status may predict the risk of cervical cancer. Selection criteria like primary testing for hrHPV and cytology as cotests before referral to colposcopy may reduce the number of unnecessary colposcopies.

Value of a catch-up HPV test in women aged 65 and above: A Danish population-based nonrandomized intervention study.

BACKGROUND: High-risk human papillomavirus (HPV) test is replacing cytology as the primary cervical cancer screening test due to superior sensitivity, but in most countries women ≥65 years have never had an HPV test despite they account for around 50% of cervical cancer deaths. We explored the effect of a catch-up HPV test among 65- to 69-year-old women without previous record of HPV-based screening. METHODS AND FINDINGS: This population-based nonrandomized intervention study (quasi-experimental design) included Danish women aged 65 to 69 with no record of cervical cancer screening in the last ≥5.5 years and no HPV-exit test at age 60 to 64 at the time of study inclusion. Eligible women residing in the Central Denmark Region were invited for HPV screening either by attending clinician-based sampling or requesting a vaginal self-sampling kit (intervention group, n = 11,192). Women residing in the remaining four Danish regions received standard care which was the opportunity to have a cervical cytology collected for whatever reason (reference group, n = 33,387). Main outcome measures were detection of cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+) per 1,000 women eligible for the screening offer and the benefit-harm ratio of the intervention and standard practice measured as the number of colposcopies needed to detect one CIN2+ case. The minimum follow-up time was 13 months for all tested women (range: 13 to 25 months). In the intervention group, 6,965 (62.2%) were screened within 12 months from the date of study inclusion and 743 (2.2%) women had a cervical cytology collected in the reference group. The CIN2+ detection was significantly higher in the intervention group (3.9, 95% confidence interval (CI): [2.9, 5.3]; p < 0.001; n = 44/11,192) as compared to the reference group (0.3, 95% CI: [0.2, 0.6]; n = 11/33,387). For the benefit-harm ratio, 11.6 (95% CI: [8.5, 15.8]; p = 0.69; n = 511/44) colposcopies were performed to detect one CIN2+ in the intervention group as compared to 10.1 (95% CI: [5.4, 18.8]; n = 111/11) colposcopies in the reference group. The study design entails a risk of confounding due to the lack of randomization. CONCLUSIONS: The higher CIN2+ detection per 1,000 eligible women in the intervention group supports that a catch-up HPV test could potentially improve cervical cancer prevention in older women. This study informs the current scientific debate as to whether women aged 65 and above should be offered a catch-up HPV test if they never had an HPV test. TRIAL REGISTRATION: ClinicalTrials.gov NCT04114968.

Levels of anxiety in women aged ≥45 years undergoing diagnostic large loop excision of the transformation zone: A longitudinal study.

OBJECTIVE: To measure anxiety levels in women aged ≥45 years undergoing diagnostic large loop excision of the transformation zone (LLETZ) at the first colposcopy visit. DESIGN: Longitudinal study. SETTING: Three colposcopy clinics in the Central Denmark Region. POPULATION: Women aged ≥45 years undergoing diagnostic LLETZ. METHODS: Women completed the State-Trait Anxiety Inventory (STAI) and Short Form 12 (mental and physical health) questionnaires before, immediately after, and at 1 and 6 months after LLETZ. MAIN OUTCOME MEASURES: STAI state anxiety median scores were calculated and stratified by health status, by letter with information about screening result and by LLETZ results. RESULTS: Of 109 eligible women, 11 were excluded, leaving 98 women for the final analyses. Response rates ranged from 84.7% to 100%. Overall, state anxiety levels were low; however, a decrease was observed from before to immediately after the LLETZ (33.4 vs 29.3, p < 0.001). The anxiety levels remained stable up to 6 months after LLETZ. Women with poor mental health were more likely to have higher anxiety levels compared with women with good mental health (before LLETZ, RR 3.77, 95% CI 2.12-6.70; 1 month after LLETZ, RR 3.37, 95% CI 1.59-7.15; 6 months after LLETZ, RR 1.93, 95%CI 1.06-3.51). CONCLUSIONS: Overall, colposcopy and diagnostic LLETZ in women aged ≥45 years were not associated with high levels of anxiety. Anxiety levels were highest before colposcopy, and the women seemed to experience immediate relief afterwards. Women with poor mental health had the highest anxiety levels throughout the study, which might call for special attention.

Clinical utility of p16/Ki67 dual-stain cytology for detection of cervical intraepithelial neoplasia grade two or worse in women with a transformation zone type 3: A cross-sectional study.

OBJECTIVE: To evaluate the clinical utility of p16/Ki67 dual-stain (DS) compared with cytology for detecting cervical intraepithelial lesion grade two or worse (CIN2+) in women with a transformation zone type 3 (TZ3). DESIGN: Cross-sectional study. SETTING: Colposcopy clinics in Central Denmark Region. POPULATION: Women aged 45 years or older referred for colposcopy because of an abnormal screening test. METHODS: All women had a cervical sample collected for cytology and DS testing and underwent large-loop excision of the transformation zone (LLETZ). MAIN OUTCOME MEASURE: Sensitivity, specificity and negative (NPV) and positive (PPV) predictive values of DS for CIN2+ detection were compared to those of cytology. RESULTS: Of 166 women eligible, 93 (56.0%) were included in the final analysis. Median age was 68 years (interquartile range [IQR] 63.4-70.5 years). Most women were postmenopausal (95.7%) and referred based on a positive human papillomavirus screening test (86.0%). Fifty-two women (55.9%) were DS-positive, 29 (55.8%) of whom had CIN2+ detected. Twenty-seven (29.0%) women had atypical squamous cells of undetermined significance or worse (ASC-US+), and CIN2+ was detected in 21 women (77.8%). DS had a higher sensitivity (96.7% versus 70.0% p = 0.021) and NPV (97.6% versus 86.4%, p = 0.018) compared with cytology for CIN2+ detection. In contrast, the specificity (63.5% versus 90.5% p < 0.001) and PPV (55.8% versus 77.8%, p = 0.001) were lower for DS compared with cytology. CONCLUSIONS: Dual stain may be a valuable risk marker to guide clinical management of women with a TZ3. The superior NPV of DS suggests that a diagnostic excision may safely be avoided in DS-negative women.

High prevalence of HPV16 and high-grade cytology in women undergoing active surveillance for cervical intraepithelial neoplasia grade 2.

INTRODUCTION: Many countries have adopted active surveillance in women with cervical intraepithelial neoplasia grade 2 (CIN2), leaving the lesion untreated. However, there is a lack of consensus on the eligibility criteria for active surveillance across countries, with some abstaining from active surveillance in women with human papilloma virus 16 (HPV16) or a high-grade cytology. Here, we aimed to describe the distribution of HPV genotypes, age, and cytology in women undergoing active surveillance for CIN2. MATERIAL AND METHODS: We conducted a single-center cross-sectional study on women aged 23-40 undergoing active surveillance for CIN2 during 2000-2010. Women were identified through the Danish Pathology Data Bank (DPDB) at Aarhus University Hospital, Denmark. We collected information on basic characteristics and results of histopathological examinations via DPDB. Women were deemed eligible for inclusion if they had a subsequent biopsy after index CIN2, and had no prior record of CIN2+, hysterectomy, or cone biopsy. Archived biopsies underwent HPV genotyping using the HPV SPF10 - DEIA-LiPA25 system, and the diagnosis was re-evaluated by three expert pathologists. We used the Chi squared-test (p-value) for comparison across groups. RESULTS: We identified 3623 women with CIN2 of whom 455 (12.6%) were included. Most women were 30 years or younger (73.8%), and half (48.8%) had a high-grade index cytology. The prevalence of any high-risk HPV was 87.0%, with HPV16 being the most prevalent genotype (35.6%). The prevalence of HPV16 was significantly higher in women aged 30 or younger (39.3%) compared to women older than 30 years (25.2%) (p = 0.006). Upon expert review, 261 (57.4%) had CIN2 confirmed, whereas 56 (12.3%) were upgraded to CIN3 and 121 (26.6%) were downgraded to CIN1/normal. While the HPV16 prevalence was similar between community and expert confirmed CIN2, the prevalence of HPV16 was significantly higher in women with expert CIN3 compared to women with expert CIN1/normal (64.3% vs. 19.0%, p = 0.001). CONCLUSIONS: The high prevalence of HPV16 and high-grade cytology imply that these women may be perceived as a high-risk population and non-eligible for active surveillance in countries outside Denmark. Future studies should investigate the importance of HPV, age, cytology, and expert review on risk of progression to help refine criteria for active surveillance.

Endocervical sampling in women with suspected cervical neoplasia: a systematic review and meta-analysis of diagnostic test accuracy studies.

OBJECTIVE: Endocervical sampling in women with suspected cervical neoplasia can be performed by either endocervical brush or endocervical curettage. This study aimed to estimate the diagnostic accuracy, discomfort, and number of inadequate samples with either test. DATA SOURCES: Four bibliographic databases were searched on June 9, 2022, with no date or language restrictions. STUDY ELIGIBILITY CRITERIA: We included all diagnostic studies and randomized clinical trials that compared the endocervical brush with endocervical curettage in women with an indication for colposcopy. METHODS: The review protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42021222406). Two authors independently screened studies, extracted data, performed the risk-of-bias assessment (Quality Assessment of Diagnostic Accuracy Studies-2), and rated the certainty of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. A meta-analysis of diagnostic test accuracy was performed using a bivariate random-effects model. RESULTS: We included 7 studies: 4 diagnostic cohort studies and 3 randomized clinical trials. The reference standard was conization or hysterectomy. Risk of bias and concern about applicability were high for some of the studies in patient selection and flow and timing. Overall pooled sensitivity was 81% (95% confidence interval, 48-95; 799 women; 7 studies; low quality of evidence) for endocervical brush and 70% (95% confidence interval, 42-89; 761 women; 7 studies; low quality of evidence) for endocervical curettage. Overall pooled specificity was 73% (95% confidence interval, 36-93; 799 women; 7 studies; low quality of evidence) for endocervical brush and 81% (95% confidence interval, 56-94; 761 women; 7 studies; low quality of evidence) for endocervical curettage. The risk ratio for inadequate samples with endocervical curettage compared with endocervical brush was 2.53 (95% confidence interval, 0.58-11.0; P=.215; low-certainty evidence). Two studies reported on patient discomfort; one found less discomfort in the endocervical brush group, and the other found no difference. CONCLUSION: No difference was found between endocervical brush and endocervical curettage in diagnostic accuracy, inadequate sampling rate, and adverse effects based on low-quality of evidence. Variation in the characteristics of women and the resulting diagnostic pathways make the external validity limited.

Cervical intraepithelial neoplasia in women with transformation zone type 3: cervical biopsy versus large loop excision.

OBJECTIVE: To compare the proportion of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) in cervical biopsies with that in large loop excision of the transformation zone (LLETZ) specimens in women aged ≥45 years with transformation zone type 3 (TZ3). DESIGN: Multicentre cross-sectional study. SETTING: Three colposcopy clinics in the Central Denmark Region. POPULATION: Women aged ≥45 years referred to colposcopy as a result of a positive human papillomavirus (HPV) test and/or abnormal cytology and with TZ3 at colposcopy. METHODS: Women had multiple biopsies taken and an LLETZ was performed. MAIN OUTCOME MEASURES: Histologically confirmed CIN2+ in biopsies compared with that in LLETZ specimens. RESULTS: Of 166 eligible women at colposcopy, 102 women with paired data from biopsies and LLETZ specimens were included for final analysis. The median age was 67.7 years (IQR 62.6-70.4 years), and most were postmenopausal (94.1%) and had undergone HPV-based screening (81.3%). The CIN2+ detection rate was significantly higher in LLETZ specimens than in biopsies (32.4% vs 14.7%, difference 17.7%, 95% CI 6.3-29.0%), resulting in more than half of CIN2+ cases being missed in biopsies (54.5%, 95% CI 36.4-71.9%). The overall agreement between biopsies and LLETZ was 82.4% (95% CI 73.6-89.2%). CONCLUSIONS: CIN2+ detection is underestimated in women aged ≥45 years with TZ3 if detection relies on the results of biopsies alone. To reduce the risk of underdiagnosis and overtreatment, future studies should explore the use of new biomarkers for risk stratification to improve discrimination between women at increased risk of CIN2+ who need to undergo LLETZ and women who may undergo follow-up.

Cervical cancer prevention among older women - challenges in screening, diagnostic workup and treatment.

Cervical cancer incidence and mortality have declined dramatically after screening for cervical cancer was implemented. Yet, studies have reported high cervical cancer incidence and mortality rates at older age despite low HPV prevalence and incidence of precursor lesions. The underlying reason for these findings remains unclear. However, it is well known that the impact of screening depends not only on the uptake and effectiveness of screening but also on the uptake and effectiveness of diagnostic workup (ie colposcopy), treatment and follow-up. In older women, sensitivity of screening and performance of colposcopy are impaired due to age-dependent changes to the cervix. In this commentary, we aimed to discuss challenges in screening and clinical management of older women, and to identify crucial areas of particular interest for future research.

Concerns about transmission, changed services and place of birth in the early COVID-19 pandemic: a national survey among Danish pregnant women. The COVIDPregDK study.

BACKGROUND: The outbreak of the COVID-19 pandemic caused great uncertainty about causes, treatment and mortality of the new virus. Constant updates of recommendations and restrictions from national authorities may have caused great concern for pregnant women. Reports suggested an increased number of pregnant women choosing to give birth at home, some even unassisted ('freebirth') due to concerns of transmission in hospital or reduction in birthplace options. During April and May 2020, we aimed to investigate i) the level of concern about coronavirus transmission in Danish pregnant women, ii) the level of concern related to changes in maternity services due to the pandemic, and iii) implications for choice of place of birth. METHODS: We conducted a nationwide cross-sectional online survey study, inviting all registered pregnant women in Denmark (n = 30,009) in April and May 2020. RESULTS: The response rate was 60% (n = 17,995). Concerns of transmission during pregnancy and birth were considerable; 63% worried about getting severely ill whilst pregnant, and 55% worried that virus would be transmitted to their child. Thirtyeight percent worried about contracting the virus at the hospital. The most predominant concern related to changes in maternity services during the pandemic was restrictions on partners' attendance at birth (81%). Especially nulliparous women were concerned about whether cancelled antenatal classes or fewer physical midwifery consultations would affect their ability to give birth or care for their child postpartum.. The proportion of women who considered a home birth was equivalent to pre-pandemic home birth rates in Denmark (3%). During the temporary discontinue of public home birth services, 18% of this group considered a home birth assisted by a private midwife (n = 125), and 6% considered a home birth with no midwifery assistance at all (n = 41). CONCLUSION: Danish pregnant womens' concerns about virus transmission to the unborn child and worries about contracting the virus during hospital appointments were considerable during the early pandemic. Home birth rates may not be affected by the pandemic, but restrictions in home birth services may impose decisions to freebirth for a small proportion of the population.

Can biopsies be omitted after normal colposcopy in women referred with low-grade cervical cytology? A prospective cohort study.

BACKGROUND: Controversy surrounds whether women with low-risk cytology screening results but a normal colposcopic assessment should have random biopsies taken. The aim of this study was to determine the yield of CIN2+ from one to four cervical biopsies in women with cytology of LSIL or ASCUS and a normal colposcopic impression. METHODS: Between January 2017 and September 2020, women over 18 years old referred for colposcopic examination due to either an abnormal smear (ASCUS+) or follow-up after previous cervical intraepithelial neoplasia (CIN) were invited to participate in the study. All study participants underwent colposcopic examination and had four biopsies taken. The biopsies were analyzed separately. RESULTS: In total, 1327 women with abnormal cervical cancer screening results or attending follow-up after a previous CIN diagnosis were enrolled in the study and examined by colposcopy. Of these, 173 were newly referred with cytology of LSIL or ASCUS and had a normal colposcopic impression and four adequate biopsies. Of these, 22.0% were diagnosed with CIN2+. When combining the results of the four biopsies, we found a 100% relative increase in CIN2+ cases compared to using only one biopsy (from 11.0% to 22.0%, P = 0.006). CONCLUSION: As we found CIN2+ from random cervical biopsies in 22.0% of women with cytology of LSIL or ASCUS who had a normal colposcopic impression, we advocate performing four random cervical biopsies at the squamocolumnar junction in such women. Trial registration NCT04249856, January 31 2020 (retrospectively registered).

Can the dynamic spectral imaging (DSI) color map improve colposcopy examination for precancerous cervical lesions? A prospective evaluation of the DSI color map in a multi-biopsy clinical setting.

BACKGROUND: Colposcopy serves as a subjective examination of the cervix with low sensitivity to detect cervical intraepithelial dysplasia (CIN) grade 2 or worse (CIN2 +). Dynamic spectral imaging (DSI) colposcopy has been developed to provide an objective element to cervix examinations and has been proven to increase sensitivity of detecting CIN2 + . We aimed to assess the performance of the DSI color map and compared it to histological diagnoses of cervical biopsies in determining the CIN grade present. METHODS: Women were included in a consecutive, prospective manner at Randers Regional Hospital, Denmark. Women were eligible to participate if they were referred for colposcopy due to abnormal cervical smear (threshold: ≥ ASCUS) or follow-up after previously diagnosed CIN. All women had four biopsies taken, one directed by colposcopists alone prior to viewing the DSI color map, one directed by the worst color on the respective DSI color map, and two additional biopsies. All biopsies were analyzed separately. We calculated sensitivity, specificity, positive predictive values, and negative predictive values (NPVs) with 95% confidence intervals (CIs). RESULTS: A total of 800 women were recruited. Of these, 529 (66.1%) were eligible for inclusion. The sensitivity of the DSI color map was found to be 48.1% (95% CI 41.1-55.1) in finding CIN grade 2 or worse (CIN2 +) when compared to the histological diagnosis of the DSI directed biopsy. This was 42.5% (95% CI 36.7-48.5) when compared to the final histological diagnosis of all four cervical biopsies and with an NPV of 53.5% (95% CI 50.5-56.5). CONCLUSION: The worst color indicated by the DSI map might not consistently reflect the true grade of cervical dysplasia present. Thus, even though the DSI color map indicates low-grade changes, colposcopists should still consider taking biopsies from the area as high-grade changes might be present. TRIAL REGISTRATION: NCT04249856, January 31 2020 (retrospectively registered).

Direct access from general practice to transvaginal ultrasound for early detection of ovarian cancer: a feasibility study.

OBJECTIVE: To investigate the feasibility of providing general practitioners (GPs) direct and fast referral access to transvaginal ultrasound (TVUS). DESIGN: A prospective cohort study. SETTING: A total of 232 Danish general practices in parts of the Central Denmark Region. SUBJECTS: Women aged ≥40 years who consulted their GP for vague and non-specific symptoms (n = 479). MAIN OUTCOME MEASURES: The feasibility assessment included the GPs' referral rate, indications for referral, management of test results, and findings from TVUS. RESULTS: A total of 479 women were referred to TVUS. The examinations revealed abnormalities in 104 (21.7%) women. Additional investigations were needed in 68 (14.2%) women of whom seven (1.5%) underwent major surgery. No case of ovarian cancer was diagnosed during the study period or the 6-month follow-up. However, three (0.6%) women with an abnormal transvaginal ultrasound were diagnosed with urogynecological cancer; this yielded a PPV of 4.4% (95% confidence interval: 1.5-12.2) and an NPV of 100.0% (95% confidence interval: 96.7-100.0) for urogynecological cancer. CONCLUSION: Providing GPs with direct access to transvaginal ultrasound was feasible; 80% of the investigated women were referred back to the GP, 14% were further investigated, 0.6% were diagnosed with urogynecological cancer, and 1.5% had major procedures performed without complications. IMPLICATIONS: Direct access to TVUS could be an important pathway to ensure fast evaluation of women presenting with vague non-specific symptoms of potential ovarian cancer. Future studies should explore the patient experience, cancer outcomes, and health economics issues.KEY POINTS Current awareness • GPs have no fast referral option for women presenting with vague non-specific symptoms that could indicate underlying ovarian cancer. Key findings • We offered GPs direct and fast referral access to TVUS; 51.7% of practices used the opportunity. • The GPs referred 479 women to TVUS; 104 had an abnormal TVUS and 68 needed additional investigations. • Seven women underwent major surgery, leading to three cases of urogynecological cancer. No woman had a false negative TVUS result.

Dynamic Spectral Imaging Colposcopy Versus Regular Colposcopy in Women Referred With High-Grade Cytology: A Nonrandomized Prospective Study.

OBJECTIVE: The aim of the study was to evaluate the sensitivity of dynamic spectral imaging (DSI) colposcopy compared with regular colposcopy for women referred with high-grade cervical cytology. METHODS: In a prospective, nonrandomized, multicenter study, we included women referred for colposcopy at hospital gynecology clinics with high-grade cytology. Women were examined using either a regular or DSI colposcope. In both groups, colposcopists located 1 area viewed as most suspicious. In the DSI group, this was done before viewing the DSI map. Subsequently, an area was chosen based on the worst color of the DSI map, and further additional biopsies were taken. All women had 4 cervical biopsies taken, all analyzed separately. The main outcome was sensitivity to find cervical intraepithelial neoplasia grade 2 or worse (CIN2+). RESULTS: A total of 261 women were examined using DSI colposcopy, and 156 women were examined using regular colposcopy. The sensitivity for finding CIN2+ when using the DSI technology as an adjunctive technology was found to be 82.2% (95% CI = 75.9-87.4), based on an average of 1.4 biopsies. This was corresponding in sensitivity to 2 biopsies taken using regular colposcopy (80.3%; 95% CI = 72.3-86.8). There was no difference in sensitivity for CIN+ between the groups when 3 or more biopsies were taken. CONCLUSIONS: We found that the DSI colposcope may help direct biopsy placement; however, the improvement is based on small differences in needed biopsies and the clinical significance of this may be small. Multiple biopsies were still superior.

Accuracy of colposcopy-directed biopsy vs dynamic spectral imaging directed biopsy in correctly identifying the grade of cervical dysplasia in women undergoing conization: A methodological study.

INTRODUCTION: Dynamic spectral imaging (DSI) colposcopy has previously been found to improve sensitivity of CIN2+ detection. The aim of this study was to compare the histological diagnosis of colposcopic-directed biopsies (CDB) with that of DSI-directed biopsies in women undergoing conization, using the histological diagnosis of the conization specimen as gold standard. MATERIAL AND METHODS: Women referred for colposcopy were included in a prospective cohort study at Randers Regional Hospital, Denmark, from January 2016 to February 2019. All women had four cervical punch biopsies taken. The first biopsy was taken from the area that appeared most abnormal by conventional colposcopy (ie, CDB) and the second biopsy from the area that appeared most abnormal using the DSI map. An additional two biopsies were taken either from other visible lesions or as random biopsies. Biopsies were analyzed separately. If any biopsies revealed cervical dysplasia of such a degree that excisional treatment was recommended, the patient was referred for conization. Subsequently, we compared the histological diagnosis of CDB and DSI-directed biopsies with that of the cone biopsy. RESULTS: A total of 573 women were enrolled, 170 of which underwent conization. In women with an adequate colposcopy and representative biopsies (n = 124) there was an overall agreement rate between the worst biopsy diagnosis (of any four) and the conization diagnosis in 95.2% (95% CI 89.8-98.2) of women. CDB diagnosis agreed with the cone diagnosis in 80.6% (95% CI 72.6-87.2) of women. DSI-directed biopsy agreed with the cone diagnosis in 83.9% (95% CI 76.2-89.9) of women. The difference in detection rate between the CDB and the DSI-directed biopsy was, however, not significant (P = .54). Taking four biopsies increases the detection rate of cervical dysplasia to 95.2%, which was a significant increase from both CDB alone (P = .0008) and DSI-directed biopsy alone (P = .0053). CONCLUSIONS: We found no significant difference in the ability to identify the cervical dysplasia grade between CDB and DSI-directed biopsies. A higher detection rate of cervical dysplasia was achieved with four biopsies than with one CDB biopsy or one DSI-directed biopsy.

Morbidity after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with carboplatin used for ovarian, tubal, and primary peritoneal cancer.

BACKGROUND AND OBJECTIVES: Hypertherm intraperitoneal chemotherapy (HIPEC) is increasingly used in the treatment of ovarian, tubal, and primary peritoneal cancer (OC). The aim was to evaluate short-term morbidity of cytoreductive surgery (CRS) and carboplatin HIPEC. METHODS: Prospective feasibility study performed from January 2016 to December 2017. Twenty-five patients with primary OC (FIGO III-IV) received upfront or interval CRS combined with carboplatin HIPEC at dose 800 mg/m 2 . Primary outcome measurements: grade 3 to 5 adverse events within 30 days according to Common Terminology Criteria for Adverse Events. Secondary outcome measurements: reoperation rate, length of hospital stay, readmission rate, and time from surgery to systemic chemotherapy administration. RESULTS: No deaths (grade 5) or grade 4 adverse events were observed. Eleven patients (44.0%) experienced at least one grade 3 adverse event, the most common being an infection (28.0%) and neutropenia (12.0%). The reoperation rate was 8.0%. The median hospital stay was 14 days (range 9-25 days), and five patients (25.0%) were readmitted within 30 days after surgery. Median time from surgery to the administration of the first dose of systemic chemotherapy was 41 days (range 24-81 days). CONCLUSION: Our small-scale prospective study supports that CRS and carboplatin HIPEC used for primary advanced-stage OC is feasible with acceptable morbidity.

A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women.

BACKGROUND: The investigational 9-valent viruslike particle vaccine against human papillomavirus (HPV) includes the HPV types in the quadrivalent HPV (qHPV) vaccine (6, 11, 16, and 18) and five additional oncogenic types (31, 33, 45, 52, and 58). Here we present the results of a study of the efficacy and immunogenicity of the 9vHPV vaccine in women 16 to 26 years of age. METHODS: We performed a randomized, international, double-blind, phase 2b-3 study of the 9vHPV vaccine in 14,215 women. Participants received the 9vHPV vaccine or the qHPV vaccine in a series of three intramuscular injections on day 1 and at months 2 and 6. Serum was collected for analysis of antibody responses. Swabs of labial, vulvar, perineal, perianal, endocervical, and ectocervical tissue were obtained and used for HPV DNA testing, and liquid-based cytologic testing (Papanicolaou testing) was performed regularly. Tissue obtained by means of biopsy or as part of definitive therapy (including a loop electrosurgical excision procedure and conization) was tested for HPV. RESULTS: The rate of high-grade cervical, vulvar, or vaginal disease irrespective of HPV type (i.e., disease caused by HPV types included in the 9vHPV vaccine and those not included) in the modified intention-to-treat population (which included participants with and those without prevalent infection or disease) was 14.0 per 1000 person-years in both vaccine groups. The rate of high-grade cervical, vulvar, or vaginal disease related to HPV-31, 33, 45, 52, and 58 in a prespecified per-protocol efficacy population (susceptible population) was 0.1 per 1000 person-years in the 9vHPV group and 1.6 per 1000 person-years in the qHPV group (efficacy of the 9vHPV vaccine, 96.7%; 95% confidence interval, 80.9 to 99.8). Antibody responses to HPV-6, 11, 16, and 18 were noninferior to those generated by the qHPV vaccine. Adverse events related to injection site were more common in the 9vHPV group than in the qHPV group. CONCLUSIONS: The 9vHPV vaccine prevented infection and disease related to HPV-31, 33, 45, 52, and 58 in a susceptible population and generated an antibody response to HPV-6, 11, 16, and 18 that was noninferior to that generated by the qHPV vaccine. The 9vHPV vaccine did not prevent infection and disease related to HPV types beyond the nine types covered by the vaccine. (Funded by Merck; ClinicalTrials.gov number, NCT00543543).

Paradoxes of follow-up - health professionals' views on follow-up after surgical treatment in gynecological cancer.

OBJECTIVE: Evidence now reveals that attending a follow-up program may not improve survival for low-stage gynecological cancer patients. The aim of this study was to explore health professionals' experiences with the follow-up programs and their views on follow-up in the future. METHODS: A qualitative approach was undertaken with semi-structured focus group interviews. Three focus group interviews were conducted at neutral ground. One group with onco-gynecologists, one group with specialist nurses, and one mixed group. The main themes of the interviewguide were: Existing follow-up program, life after cancer and future follow-up. The interviews were transcribed verbatim. Patterns and themes were uncovered from the data inspired by interpretive description. RESULTS: The doctors described most advantages, such as: Quality control of their own work, detection of sequelae after surgery, and credit and appraisal from the patients. A disadvantage was the inadequate use of the nurses' main competencies. Some dilemmas were described by the nurses as well as doctors: First, both groups were aware of the existing evidence that attendance of follow-up programs may not improve survival and yet, health professionals still performed the follow-ups and most often did not address this paradox for the patients. Second, the existing follow-up program seemed to bring the patients comfort and security on one hand, but on the other hand it seemed to induce insecurity and anxiety. The health professionals agreed that future follow-up should be individualized with focus on the single patients' needs and psychological wellbeing. The health professionals identified a great challenge in communicating the evidence and the forthcoming changes in the follow-up programs to the patients. CONCLUSIONS: This study revealed that the existing follow-up regime contains several dilemmas. According to the health professionals, future follow-up must be more individualized, and a shift in focus is needed from relapse to quality of life after cancer.