Quality of training in cervical cancer radical surgery: a survey from the European Network of Young Gynaecologic Oncologists (ENYGO).

BACKGROUND: The European Society of Gynaecological Oncology (ESGO) and partners are committed to improving the training for gynecologic oncology fellows. The aim of this survey was to assess the type and level of training in cervical cancer surgery and to investigate whether the Laparoscopic Approach to Cervical Cancer (LACC) trial results impacted training in radical surgery for gynecologic oncology fellows. METHODS: In June 2020, a 47-question electronic survey was shared with European Network of Young Gynaecologic Oncologists (ENYGO) members. Specialist fellows in obstetrics and gynecology, and gynecologic oncology, from high- and low-volume centers, who started training between January 1, 2017 and January 1, 2020 or started before January 1, 2017 but finished their training at least 6 months after the LACC trial publication (October 2018), were included. RESULTS: 81 of 125 (64.8%) respondents were included. The median time from the start of the fellowship to completion of the survey was 28 months (range 6-48). 56 (69.1%) respondents were still fellows-in-training. 6 of 56 (10.7%) and 14 of 25 (56.0%) respondents who were still in training and completed the fellowship, respectively, performed ≥10 radical hysterectomies during their training. Fellows trained in an ESGO accredited center had a higher chance to perform sentinel lymph node biopsy (60.4% vs 30.3%; p=0.027). There was no difference in the mean number of radical hysterectomies performed by fellows during fellowship before and after the LACC trial publication (8±12.0 vs 7±8.4, respectively; p=0.46). A significant reduction in number of minimally invasive radical hysterectomies was noted when comparing the period before and after the LACC trial (38.5% vs 13.8%, respectively; p<0.001). CONCLUSION: Exposure to radical surgery for cervical cancer among gynecologic oncology fellows is low. Centralization of cervical cancer cases to high-volume centers may provide an increase in fellows' exposure to radical procedures. The LACC trial publication was associated with a decrease in minimally invasive radical hysterectomies performed by fellows.

Prognostic value of radiological recurrence patterns in ovarian cancer.

OBJECTIVE: To study the prognostic value of CT assessed recurrence patterns on survival outcomes in women with epithelial ovarian cancer. METHODS: CT scans were systematically re-evaluated on predefined anatomical sites for the presence of tumor in all 89 patients diagnosed with epithelial ovarian cancer between January 2008 and December 2013 who underwent cytoreductive surgery at our institution and developed a recurrence. A Cox proportional hazard analysis was used to test the effect of recurrence patterns on survival. RESULTS: The median survival time for patients grouped as predominantly intraperitoneal (n = 62), hematogenous (n = 13) or lymphatic (n = 14) recurrence was 25.8 (95% CI 18.4-33.2), 27.6 (95% CI 18.5-36.6) and 52.9 months (95% CI 42.1-63.7), respectively. Univariate Cox regression analysis identified the following prognostic factors: lymphatic recurrence pattern (HR 0.42, 95% CI 0.21-0.85), ascites at diagnosis (HR 2.35, 95% CI 1.46-3.79), residual tumor at initial surgery (HR 2.16, 95% CI 1.36-3.44) and FIGO stage (I-IIIB: HR 0.59, 95% CI 0.33-1.06). The median time to recurrence was 19.5 month for patients after complete debulking surgery, 13.1 months for patients with residual disease ≤1 cm and 8.2 months for patients with residual disease >1 cm after surgery (P < 0.001). No differences in recurrence patterns between patients with complete and incomplete surgery were found. CONCLUSIONS: Prolonged survival rates were found in ovarian cancer patients with a predominantly lymphatic recurrence compared to patients with a predominantly peritoneal or hematogenous recurrence. Completeness of surgery was associated with time to recurrence. Classification of recurrence patterns can help counsel patients on their prognosis at the time of recurrence.

Neoadjuvant chemotherapy versus debulking surgery in advanced tubo-ovarian cancers: pooled analysis of individual patient data from the EORTC 55971 and CHORUS trials.

BACKGROUND: Individual patient data from two randomised trials comparing neoadjuvant chemotherapy with upfront debulking surgery in advanced tubo-ovarian cancer were analysed to examine long-term outcomes for patients and to identify any preferable therapeutic approaches for subgroup populations. METHODS: We did a per-protocol pooled analysis of individual patient data from the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial (NCT00003636) and the Medical Research Council Chemotherapy Or Upfront Surgery (CHORUS) trial (ISRCTN74802813). In the EORTC trial, eligible women had biopsy-proven International Federation of Gynecology and Obstetrics (FIGO) stage IIIC or IV invasive epithelial tubo-ovarian carcinoma. In the CHORUS trial, inclusion criteria were similar to those of the EORTC trial, and women with apparent FIGO stage IIIA and IIIB disease were also eligible. The main aim of the pooled analysis was to show non-inferiority in overall survival with neoadjuvant chemotherapy compared with upfront debulking surgery, using the reverse Kaplan-Meier method. Tests for heterogeneity were based on Cochran's Q heterogeneity statistic. FINDINGS: Data for 1220 women were included in the pooled analysis, 670 from the EORTC trial and 550 from the CHORUS trial. 612 women were randomly allocated to receive upfront debulking surgery and 608 to receive neoadjuvant chemotherapy. Median follow-up was 7·6 years (IQR 6·0-9·6; EORTC, 9·2 years [IQR 7·3-10·4]; CHORUS, 5·9 years [IQR 4·3-7·4]). Median age was 63 years (IQR 56-71) and median size of the largest metastatic tumour at diagnosis was 8 cm (IQR 4·8-13·0). 55 (5%) women had FIGO stage II-IIIB disease, 831 (68%) had stage IIIC disease, and 230 (19%) had stage IV disease, with staging data missing for 104 (9%) women. In the entire population, no difference in median overall survival was noted between patients who underwent neoadjuvant chemotherapy and upfront debulking surgery (27·6 months [IQR 14·1-51·3] and 26·9 months [12·7-50·1], respectively; hazard ratio [HR] 0·97, 95% CI 0·86-1·09; p=0·586). Median overall survival for EORTC and CHORUS patients was significantly different at 30·2 months (IQR 15·7-53·7) and 23·6 months (10·5-46·9), respectively (HR 1·20, 95% CI 1·06-1·36; p=0·004), but was not heterogeneous (Cochran's Q, p=0·17). Women with stage IV disease had significantly better outcomes with neoadjuvant chemotherapy compared with upfront debulking surgery (median overall survival 24·3 months [IQR 14·1-47·6] and 21·2 months [10·0-36·4], respectively; HR 0·76, 95% CI 0·58-1·00; p=0·048; median progression-free survival 10·6 months [7·9-15·0] and 9·7 months [5·2-13·2], respectively; HR 0·77, 95% CI 0·59-1·00; p=0·049). INTERPRETATION: Long-term follow-up data substantiate previous results showing that neoadjuvant chemotherapy and upfront debulking surgery result in similar overall survival in advanced tubo-ovarian cancer, with better survival in women with stage IV disease with neoadjuvant chemotherapy. This pooled analysis, with long-term follow-up, shows that neoadjuvant chemotherapy is a valuable treatment option for patients with stage IIIC-IV tubo-ovarian cancer, particularly in patients with a high tumour burden at presentation or poor performance status. FUNDING: National Cancer Institute and Vlaamse Liga tegen kanker (Flemish League against Cancer).

The Society of European Robotic Gynaecological Surgery (SERGS) Pilot Curriculum for robot assisted gynecological surgery.

PURPOSE: To set forth experiences in the context of the SERGS Pilot Curriculum-the first standardized educational program for robotic use in gynecological surgery-in terms of feasibility, effectiveness and potential for certification. METHODS: The Society of European Robotic Gynecological Surgery (SERGS) outlined a Pilot Curriculum for standardized education in robot-assisted laparoscopic gynecological surgery. Its feasibility and acceptance were checked in the form of a fellowship pilot program conducted at four European Centers of Excellence for robot-assisted surgery. Results and conclusions derived from this pilot program are presented. RESULTS: The SERGS Pilot Curriculum defines criteria for a standardized training and assessment of performance, boosts the learning curve of the candidate and increases contentment at work. Regarding face validity, it proves valuable as finally all candidates could perform the outlined procedure safely and efficiently without supervision. CONCLUSION: Due to the immense increase of robotic procedures in gynecology standardized training curricula are indispensable. This seems highly necessary to ensure patients' safety and surgical outcome. The SERGS Pilot Curriculum sets standards for a stepwise theoretical and practical training in gynecological robotic procedures. It seems feasible as instrument for accreditation as gynecologic robotic surgeon. Though as a general applicable guideline for systematic training in robot-assisted surgery, a definite curriculum should have a more definite timeline and implementation of a structured assessment of performance.

Good performance of p16/ki-67 dual-stained cytology for surveillance of women treated for high-grade CIN.

Women treated for high-grade cervical intraepithelial neoplasia (CIN) are at risk of recurrent CIN Grade 2 or worse (rCIN2+). Currently, posttreatment monitoring is performed using cytology or cytology/high-risk (hr)HPV cotesting. This study aimed to evaluate the performance of p16/Ki-67 dual-stained cytology (p16/Ki-67) for posttreatment monitoring. Three hundred and twenty-three women treated for high-grade CIN in the SIMONATH study underwent close surveillance by cytology, hrHPV and DNA methylation marker testing up to 12 months posttreatment. Histological endpoints were ascertained by colposcopy with biopsy at 6 and/or 12 months. p16/Ki-67 dual-staining was performed on residual liquid-based cytology samples obtained at, or shortly before biopsy collection. Clinical performance estimates of cytology, hrHPV, p16/Ki-67 testing and combinations thereof for the detection of rCIN2+ were determined and compared to each other. Sensitivity of p16/Ki-67 for rCIN2+ (69.2%) was nonsignificantly lower than that of cytology (82.1%; ratio 0.84, 95% CI: 0.71-1.01), but significantly lower than that of hrHPV testing (84.6%; ratio 0.82, 95% CI: 0.68-0.99). Specificity of p16/Ki-67 for rCIN2+ (90.4%) was significantly higher compared to both cytology (70.8%; ratio 1.28, 95% CI: 1.19-1.37) and hrHPV testing (76.2%; ratio 1.19, 95% CI: 1.12-1.26). Overall, hrHPV testing showed very high sensitivity, along with a good specificity. When considering cotesting, combined p16/Ki-67/hrHPV testing showed rCIN2+ sensitivity comparable to cytology/hrHPV cotesting (87.2% vs. 89.7%; ratio 0.97, 95% CI: 0.92-1.03), but with significantly increased specificity (74.2% vs. 58.1%; ratio 1.28, 95% CI: 1.19-1.38). Thus, when considered in combination with hrHPV, p16/Ki-67 might be an attractive approach for surveillance of women treated for high-grade CIN.

High-resolution T2-weighted cervical cancer imaging: a feasibility study on ultra-high-field 7.0-T MRI with an endorectal monopole antenna.

OBJECTIVES: We studied the feasibility of high-resolution T2-weighted cervical cancer imaging on an ultra-high-field 7.0-T magnetic resonance imaging (MRI) system using an endorectal antenna of 4.7-mm thickness. METHODS: A feasibility study on 20 stage IB1-IIB cervical cancer patients was conducted. All underwent pre-treatment 1.5-T MRI. At 7.0-T MRI, an external transmit/receive array with seven dipole antennae and a single endorectal monopole receive antenna were used. Discomfort levels were assessed. Following individualised phase-based B1+ shimming, T2-weighted turbo spin echo sequences were completed. RESULTS: Patients had stage IB1 (n = 9), IB2 (n = 4), IIA1 (n = 1) or IIB (n = 6) cervical cancer. Discomfort (ten-point scale) was minimal at placement and removal of the endorectal antenna with a median score of 1 (range, 0-5) and 0 (range, 0-2) respectively. Its use did not result in adverse events or pre-term session discontinuation. To demonstrate feasibility, T2-weighted acquisitions from 7.0-T MRI are presented in comparison to 1.5-T MRI. Artefacts on 7.0-T MRI were due to motion, locally destructive B1 interference, excessive B1 under the external antennae and SENSE reconstruction. CONCLUSIONS: High-resolution T2-weighted 7.0-T MRI of stage IB1-IIB cervical cancer is feasible. The addition of an endorectal antenna is well tolerated by patients. KEY POINTS: • High resolution T 2 -weighted 7.0-T MRI of the inner female pelvis is challenging • We demonstrate a feasible approach for T 2 -weighted 7.0-T MRI of cervical cancer • An endorectal monopole receive antenna is well tolerated by participants • The endorectal antenna did not lead to adverse events or session discontinuation.

Robotic and Advanced Laparoscopic Surgical Training in European Gynecological Oncology Trainees.

INTRODUCTION: Advanced minimal access surgical training is an important component of training in gynecological oncology (GO). Europe-wide data on this topic are lacking. We present data on availability and trainee experience of advanced laparoscopic surgical (ALS) and robotic surgical (RS) training in GO across Europe. METHOD: A prospective web-based anonymized survey of European GO trainees was sent to the European Network of Young Gynaecological Oncologists members/trainees. It included sociodemographic information and specific questions pertaining to training experience or satisfaction in laparoscopic and robotic surgery. χ test was used for evaluating categorical variables and Mann-Whitney/Kruskal-Wallis (nonparametric) tests for continuous variables between 2 and more independent groups. RESULTS: A total of 113 GO trainees from 29 countries responded. The mean (standard deviation) age was 35.2 (6.1) years, 59.3% were men, 40.7% were women, and 46% were in accredited training posts. The ALS and RS training was offered in only 43% and 23% of institutes respectively, and 54% and 23% of trainees had undergone some form of formal or informal training in ALS and RS respectively. A total of 62.4% felt that RS should be a formal component of GO training programs. A total of 61% and 35% planned to go outside their institute for ALS or RS training respectively. Trainees rating (1-5 scale) of their open surgery and ALS or RS skills (3.3/2.6/1.9) and training experience (3.5/2.8/2.1), respectively, were higher for open surgery than ALS or RS (P < 0.0005). Accredited posts were more likely than nonaccredited posts to offer ALS training (60%/31%, P = 0.002), formal training schedules (27.9%/4.4%, P = 0.003), and use of logbooks (46%/23%, P = 0.035). CONCLUSIONS: Training and experience in ALS and RS are poorly rated by GO trainees across Europe, and only few centers offer this. There is an urgent need to expand and harmonize training opportunities for ALS and RS. Most trainees want RS included as a formal component of their training.

Comparing the performance of FAM19A4 methylation analysis, cytology and HPV16/18 genotyping for the detection of cervical (pre)cancer in high-risk HPV-positive women of a gynecologic outpatient population (COMETH study).

Recently, DNA methylation analysis of FAM19A4 in cervical scrapes has been shown to adequately detect high-grade cervical intraepithelial neoplasia and cervical cancer (≥ CIN3) in high-risk HPV (hrHPV)-positive women. Here, we compared the clinical performance of FAM19A4 methylation analysis to cytology and HPV16/18 genotyping, separately and in combination, for ≥ CIN3 detection in hrHPV-positive women participating in a prospective observational multi-center cohort study. The study population comprised hrHPV-positive women aged 18-66 years, visiting a gynecological outpatient clinic. From these women, cervical scrapes and colposcopy-directed biopsies (for histological confirmation) were obtained. Cervical scrapes were analyzed for FAM19A4 gene promoter methylation, cytology and HPV16/18 genotyping. Methylation analysis was performed by quantitative methylation-specific PCR (qMSP). Sensitivities and specificities for ≥ CIN3 were compared between tests. Stratified analyses were performed for variables that potentially influence marker performance. Of all 508 hrHPV-positive women, the sensitivities for ≥ CIN3 of cytology, FAM19A4 methylation analysis, and cytology combined with HPV16/18 genotyping were 85.6, 75.6 and 92.2%, respectively, with corresponding specificities of 49.8, 71.1 and 29.4%, respectively. Both sensitivity and specificity of FAM19A4 methylation analysis were associated with age (p ≤ 0.001 each). In women ≥ 30 years (n = 287), ≥ CIN3 sensitivity of FAM19A4 methylation analysis was 88.3% (95%CI: 80.2-96.5) which was noninferior to that of cytology [85.5% (95%CI: 76.0-94.0)], at a significantly higher specificity [62.1% (95%CI: 55.8-68.4) compared to 47.6% (95%CI: 41.1-54.1)]. In conclusion, among hrHPV-positive women from an outpatient population aged ≥ 30 years, methylation analysis of FAM19A4 is an attractive marker for the identification of women with ≥ CIN3.

FAM19A4 methylation analysis in self-samples compared with cervical scrapes for detecting cervical (pre)cancer in HPV-positive women.

BACKGROUND: High-risk human papillomavirus (hrHPV)-positive women require triage to identify those with cervical high-grade intraepithelial neoplasia and cancer (⩾CIN3 (cervical intraepithelial neoplasia grade 3)). FAM19A4 methylation analysis, which detects advanced CIN and cancer, is applicable to different sample types. However, studies comparing the performance of FAM19A4 methylation analysis in hrHPV-positive self-samples and paired physician-taken scrapes are lacking. METHODS: We compared the performance of FAM19A4 methylation analysis (and/or HPV16/18 genotyping) in self-samples and paired physician-taken scrapes for ⩾CIN3 detection in hrHPV-positive women (n=450,18-66 years). RESULTS: Overall FAM19A4 methylation levels between sample types were significantly correlated, with strongest correlation in women with ⩾CIN3 (Spearman's ρ 0.697, P<0.001). The performance of FAM19A4 methylation analysis and/or HPV16/18 genotyping did not differ significantly between sample types. In women ⩾30 years, ⩾CIN3 sensitivity of FAM19A4 methylation analysis was 78.4% in self-samples and 88.2% in scrapes (ratio 0.89; CI: 0.75-1.05). In women <30 years, ⩾CIN3 sensitivities were 37.5% and 45.8%, respectively (ratio 0.82; CI: 0.55-1.21). In both groups, ⩾CIN3 specificity of FAM19A4 methylation analysis was significantly higher in self-samples compared with scrapes. CONCLUSIONS: FAM19A4 methylation analysis in hrHPV-positive self-samples had a slightly lower sensitivity and a higher specificity for ⩾CIN3 compared with paired physician-taken scrapes. With a similarly good clinical performance in both sample types, combined FAM19A4 methylation analysis and HPV16/18 genotyping provides a feasible triage strategy for hrHPV-positive women, with direct applicability on self-samples.

p16/Ki-67 dual-stained cytology for detecting cervical (pre)cancer in a HPV-positive gynecologic outpatient population.

Women who test positive for a high-risk type of the human papillomavirus (HPV) require triage testing to identify those women with cervical intraepithelial neoplasia grade 3 or cancer (≥CIN3). Although Pap cytology is considered an attractive triage test, its applicability is hampered by its subjective nature. This study prospectively compared the clinical performance of p16/Ki-67 dual-stained cytology to that of Pap cytology, with or without HPV16/18 genotyping, in high-risk HPV-positive women visiting gynecologic outpatient clinics (n=446 and age 18-66 years). From all women, cervical scrapes (for Pap cytology, HPV16/18 genotyping, and p16/Ki-67 dual-stained cytology) and colposcopy-directed biopsies were obtained. The sensitivity of p16/Ki-67 dual-stained cytology for ≥CIN3 (93.8%) did neither differ significantly from that of Pap cytology (87.7%; ratio 1.07 and 95% confidence interval (CI): 0.97-1.18) nor from that of Pap cytology combined with HPV16/18 genotyping (95.1%; ratio 0.99 and 95% CI: 0.91-1.07). However, the specificity of p16/Ki-67 dual-stained cytology for ≥CIN3 (51.2%) was significantly higher than that of Pap cytology (44.9%; ratio 1.14 and 95% CI: 1.01-1.29) and Pap cytology combined with HPV16/18 genotyping (25.8%; ratio 1.99 and 95% CI: 1.68-2.35). After exclusion of women who had been referred because of abnormal Pap cytology, the specificity of p16/Ki-67 dual-stained cytology for ≥CIN3 (56.7%) remained the same, whereas that of Pap cytology (60.3%) increased substantially, resulting in a similar specificity of both assays (ratio 0.94 and 95% CI: 0.83-1.07) in this sub-cohort. In summary, p16/Ki-67 dual-stained cytology has a good clinical performance and is an interesting objective microscopy-based triage tool for high-risk HPV-positive women.

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

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.

Clinical Use of Cancer Biomarkers in Epithelial Ovarian Cancer: Updated Guidelines From the European Group on Tumor Markers.

OBJECTIVE: To present an update of the European Group on Tumor Markers guidelines for serum markers in epithelial ovarian cancer. METHODS: Systematic literature survey from 2008 to 2013. The articles were evaluated by level of evidence and strength of recommendation. RESULTS: Because of its low sensitivity (50-62% for early stage epithelial ovarian cancer) and limited specificity (94-98.5%), cancer antigen (CA) 125 (CA125) is not recommended as a screening test in asymptomatic women. The Risk of Malignancy Index, which includes CA125, transvaginal ultrasound, and menopausal status, is recommended for the differential diagnosis of a pelvic mass. Because human epididymis protein 4 has been reported to have superior specificity to CA125, especially in premenopausal women, it may be considered either alone or as part of the risk of ovarian malignancy algorithm, in the differential diagnosis of pelvic masses, especially in such women. CA125 should be used to monitor response to first-line chemotherapy using the previously published criteria of the Gynecological Cancer Intergroup, that is, at least a 50% reduction of a pretreatment sample of 70 kU/L or greater. The value of CA125 in posttherapy surveillance is less clear. Although a prospective randomized trial concluded that early administration of chemotherapy based on increasing CA125 levels had no effect on survival, European Group on Tumor Markers state that monitoring with CA125 in this situation should occur, especially if the patient is a candidate for secondary cytoreductive surgery. CONCLUSIONS: At present, CA125 remains the most important biomarker for epithelial ovarian cancer, excluding tumors of mucinous origin.

Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 4-year interim follow-up of the phase 3, double-blind, randomised controlled VIVIANE study.

BACKGROUND: Although adolescent girls are the main population for prophylactic human papillomavirus (HPV) vaccines, adult women who remain at risk of cervical cancer can also be vaccinated. We report data from the interim analysis of the ongoing VIVIANE study, the aim of which is to assess the efficacy, safety, and immunogenicity of the HPV 16/18 AS04-adjuvanted vaccine in adult women. METHODS: In this phase 3, multinational, double-blind, randomised controlled trial, we randomly assigned healthy women older than 25 years to the HPV 16/18 vaccine or control (1:1), via an internet-based system with an algorithm process that accounted for region, age stratum, baseline HPV DNA status, HPV 16/18 serostatus, and cytology. Enrolment was age-stratified, with about 45% of participants in each of the 26-35 and 36-45 years age strata and 10% in the 46 years and older stratum. Up to 15% of women in each age stratum could have a history of HPV infection or disease. The primary endpoint was vaccine efficacy against 6-month persistent infection or cervical intraepithelial neoplasia grade 1 or higher (CIN1+) associated with HPV 16/18. The primary analysis was done in the according-to-protocol cohort for efficacy, which consists of women who received all three vaccine or control doses, had negative or low-grade cytology at baseline, and had no history of HPV disease. Secondary analyses included vaccine efficacy against non-vaccine oncogenic HPV types. Mean follow-up time was 40·3 months. This study is registered with ClinicalTrials.gov, number NCT00294047. FINDINGS: The first participant was enrolled on Feb 16, 2006, and the last study visit for the present analysis took place on Dec 10, 2010; 5752 women were included in the total vaccinated cohort (n=2881 vaccine, n=2871 control), and 4505 in the according-to-protocol cohort for efficacy (n=2264 vaccine, n=2241 control). Vaccine efficacy against HPV 16/18-related 6-month persistent infection or CIN1+ was significant in all age groups combined (81·1%, 97·7% CI 52·1-94·0), in the 26-35 years age group (83·5%, 45·0-96·8), and in the 36-45 years age group (77·2%, 2·8-96·9); no cases were seen in women aged 46 years and older. Vaccine efficacy against atypical squamous cells of undetermined significance or greater associated with HPV 16/18 was also significant. We also noted significant cross-protective vaccine efficacy against 6-month persistent infection with HPV 31 (79·1%, 97·7% CI 27·6-95·9) and HPV 45 (76·9%, 18·5-95·6]) Serious adverse events occurred in 285 (10%) of 2881 women in the vaccine group and 267 (9%) of 2871 in the control group; five (<1%) and eight (<1%) of these events, respectively, were believed to be related to vaccination. INTERPRETATION: In women older than 25 years, the HPV 16/18 vaccine is efficacious against infections and cervical abnormalities associated with the vaccine types, as well as infections with the non-vaccine HPV types 31 and 45. FUNDING: GlaxoSmithKline Biologicals SA.

The diagnostic process of cervical cancer; areas of good practice, and windows of opportunity.

OBJECTIVE: Despite an extensive screening programme in The Netherlands, some cases of cervical cancer are still diagnosed in late stages of disease. The aim of the present study was to investigate which elements in the diagnostic process of cervical cancer may be improved. METHODS: This is a retrospective study of 120 patients with cervical cancer diagnosed between January 1st 2008 and June 1st 2010 at the University Medical Center Utrecht. Patient charts, referral information, and pathology results were analyzed. RESULTS: 39.1% of cancer cases were screen or interval detected; the other 60.9% of patients had not been screened, either due to non-attendance or because they fell outside the age range for screening. The final diagnosis of cervical cancer was established by biopsy in 77 (64.2%) and by excision of the cervical transformation zone in 35 (29.2%) of the patients. Fifteen (43%) of these excisions could have been avoided if biopsies would have been taken at the first examination, and had shown invasive cancer. CONCLUSIONS: Cervical cancer screening aims at early detection of precursor lesions to decrease the incidence of cancer. This in-depth analysis suggests that improvement of quality of care is to be expected from correct recognition of cervical cancer by physicians and adjustments of the screening programme to reach younger women and non-responders.

The work place educational climate in gynecological oncology fellowships across Europe: the impact of accreditation.

BACKGROUND: A good educational climate/environment in the workplace is essential for developing high-quality medical (sub)specialists. These data are lacking for gynecological oncology training. OBJECTIVE: This study aims to evaluate the educational climate in gynecological oncology training throughout Europe and the factors affecting it. METHODS: A Web-based anonymous survey sent to ENYGO (European Network of Young Gynecological Oncologists) members/trainees to assess gynecological oncology training. This included sociodemographic information, details regarding training posts, and a 50-item validated Dutch Residency Educational Climate Test (D-RECT) questionnaire with 11 subscales (1-5 Likert scale) to assess the educational climate. The χ test was used for evaluating categorical variables, and the Mann-Whitney U (nonparametric) test was used for continuous variables between 2 independent groups. Cronbach α assessed the questionnaire reliability. Multivariable linear regression assessed the effect of variables on D-RECT outcome subscales. RESULTS: One hundred nineteen gynecological oncological fellows responded. The D-RECT questionnaire was extremely reliable for assessing the educational environment in gynecological oncology (subscales' Cronbach α, 0.82-0.96). Overall, trainees do not seem to receive adequate/effective constructive feedback during training. The overall educational climate (supervision, coaching/assessment, feedback, teamwork, interconsultant relationships, formal education, role of the tutor, patient handover, and overall consultant's attitude) was significantly better (P = 0.001) in centers providing accredited training in comparison with centers without such accreditation. Multivariable regression indicated the main factors independently associated with a better educational climate were presence of an accredited training post and total years of training. CONCLUSIONS: This study emphasizes the need for better feedback mechanisms and the importance of accreditation of centers for training in gynecological oncology to ensure training within higher quality clinical learning climates.

The Value of Endocervical Curettage in Addition to Biopsies in Women Referred to Colposcopy.

OBJECTIVE: Performing endocervical curettage (ECC) at colposcopy may increase the yield of cervical intraepithelial neoplasia grade 2 (CIN2) or worse (CIN2+) compared to biopsies alone. The additional benefit of ECC in detecting CIN2+ was studied in women with lesion-targeted biopsies (low-grade or worse impression) and women with biopsies of normal-appearing cervix (less than low-grade impression). METHODS: In this subanalysis of a multicenter study, 126 women referred to colposcopy who had an ECC were included. Multiple directed biopsies were taken from lesions, and a nontargeted biopsy was added if fewer than 4 biopsies were collected. Risk strata of CIN2+ were evaluated based on cytology and colposcopic appearance to identify women for whom ECC would be most valuable. RESULTS: The CIN2+ yield of ECC in addition to biopsies was 15 (11.9%) of 126. In women with lesion-targeted biopsies and ECC, the CIN2+ yield of targeted biopsies was 34 (51.5%) of 66, the yield of additional nontargeted biopsies was 1 (1.5%) of 66, and the additional CIN2+ yield of ECC was 5 (7.6%) of 66. The yield in women with nontargeted biopsies only and ECC was 5 (8.3%) 60, and the additional yield for ECC was 10 (16.7%) of 60. Endocervical curettage did not find disease in women with atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion. CONCLUSIONS: In women with less than low-grade impression and especially those with unsatisfactory colposcopy, the yield of CIN2+ was higher for ECC compared to nontargeted biopsies. The highest yield of CIN2+ from ECC was observed in women with high-grade squamous intraepithelial lesion and less than low-grade impression, suggesting that disease is higher up in the endocervix in this group.

Pelvic lymphadenectomy improves survival in patients with cervical cancer with low-volume disease in the sentinel node: a retrospective multicenter cohort study.

OBJECTIVE: In this study, we aimed to describe the value of pelvic lymph node dissection (LND) after sentinel lymph node (SN) biopsy in early-stage cervical cancer. METHODS: We performed a retrospective multicenter cohort study in 8 gynecological oncology departments. In total, 645 women with International Federation of Gynecology and Obstetrics stage IA to IIB cervical cancer of squamous, adeno, or adenosquamous histologic type who underwent SN biopsy followed by pelvic LND were enrolled in this study. Radioisotope tracers and blue dye were used to localize the sentinel node, and pathologic ultrastaging was performed. RESULTS: Among the patients with low-volume disease (micrometastases and isolated tumor cells) in the sentinel node, the overall survival was significantly better (P = 0.046) if more than 16 non-SNs were removed. No such significant difference in survival was detected in patients with negative or macrometastatic sentinel nodes. CONCLUSIONS: Our findings indicate that in patients with negative or macrometastatic disease in the sentinel nodes, an additional LND did not alter survival. Conversely, our data suggest that the survival of patients with low-volume disease is improved when more than 16 additional lymph nodes are removed. If in a prospective trial our data are confirmed, we would suggest a 2-stage operation.

Epithelial ovarian cancer: rationale for changing the one-fits-all standard treatment regimen to subtype-specific treatment.

OBJECTIVE: Epithelial ovarian cancers (EOCs) are, although still treated as a single disease entity, often classified into type I tumors (low-grade serous, mucinous, endometrioid, clear cell) and type II tumors (high-grade serous, undifferentiated cancers, carcinosarcomas). The aim of our study was to determine the incidence, clinical relevance, and prognostic and predictive impact of somatic mutations in both types I and II EOCs. METHODS: Two hundred sixty-two evaluable, primary, high-risk stage I (grade 3, or aneuploid grade 1 or 2, or clear cell) and stage II-IV EOCs, collected at the University Hospitals Leuven and within the European Organisation for Research and Treatment of Cancer 55971 trial, were genotyped for hotspot mutations in KRAS (COSMIC [Catalogue of Somatic Mutations in Cancer] coverage >97%), BRAF (>94%), NRAS (>97%), PIK3CA (>79%), PTEN, FBXW7 (>57%), AKT2, AKT3, and FOXL2, using Sequenom MassARRAY. RESULTS: Of the 13% histopathologically classified type I tumors, 49% were KRAS or PIK3CA mutant versus only 2.9% in the type II tumors (87%). Mucinous subtypes harbored significantly more KRAS mutations than all nonmucinous tumors (50% vs 4%, P < 0.001). PIK3CA mutations were predominantly found in clear cell carcinomas (46.2%) and endometrioid carcinoma (20%) and were frequently associated with endometriosis. Moreover, low-grade serous tumors were more frequently KRAS or BRAF mutated (44%) than high-grade serous tumors (0.6%). KRAS or PIK3CA mutation did not correlate with progression-free survival or overall survival. Mutations in NRAS, PTEN, FBXW7, AKT2, AKT3, and FOXL2 were rare (<1%). CONCLUSIONS: Somatic mutations are rare in type II EOCs, whereas type I EOCs contain distinct diseases with different driver mutations. In general, these tumors respond worse to standard paclitaxel carboplatin therapy. Clinical trials with molecular targeted therapy in the different subtypes of type I tumors are urgently needed using this theragnostic information.

Validation of a novel virtual reality simulator for robotic surgery.

OBJECTIVE: With the increase in robotic-assisted laparoscopic surgery there is a concomitant rising demand for training methods. The objective was to establish face and construct validity of a novel virtual reality simulator (dV-Trainer, Mimic Technologies, Seattle, WA) for the use in training of robot-assisted surgery. METHODS: A comparative cohort study was performed. Participants (n = 42) were divided into three groups according to their robotic experience. To determine construct validity, participants performed three different exercises twice. Performance parameters were measured. To determine face validity, participants filled in a questionnaire after completion of the exercises. RESULTS: Experts outperformed novices in most of the measured parameters. The most discriminative parameters were "time to complete" and "economy of motion" (P < 0.001). The training capacity of the simulator was rated 4.6 ± 0.5 SD on a 5-point Likert scale. The realism of the simulator in general, visual graphics, movements of instruments, interaction with objects, and the depth perception were all rated as being realistic. The simulator is considered to be a very useful training tool for residents and medical specialist starting with robotic surgery. CONCLUSIONS: Face and construct validity for the dV-Trainer could be established. The virtual reality simulator is a useful tool for training robotic surgery.