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.

Familial Occurrence of Adult Granulosa Cell Tumors: Analysis of Whole-Genome Germline Variants.

Adult granulosa cell tumor (AGCT) is a rare ovarian cancer subtype, with a peak incidence around 50-55 years. Although AGCT can occur in specific syndromes, a genetic predisposition for AGCT has not been identified. The aim of this study is to identify a genetic variant in families with AGCT patients, potentially contributing to tumor evolution. We identified four families, each including two women diagnosed with AGCT. Whole-genome sequencing was performed to identify overlapping germline variants or affected genes. Familial relationship was evaluated using genealogy and genomic analyses. Patient characteristics, medical (family) history, and pedigrees were collected. Findings were compared to a reference group of 33 unrelated AGCT patients. Mean age at diagnosis was 38 years (range from 17 to 60) versus 51 years in the reference group, and seven of eight patients were premenopausal. In two families, three first degree relatives were diagnosed with breast cancer. Furthermore, polycystic ovary syndrome (PCOS) and subfertility was reported in three families. Predicted deleterious variants in PIK3C2G, BMP5, and LRP2 were identified. In conclusion, AGCTs occur in families and could potentially be hereditary. In these families, the age of AGCT diagnosis is lower and cases of breast cancer, PCOS, and subfertility are present. We could not identify an overlapping genetic variant or affected locus that may explain a genetic predisposition for AGCT.

EBCOG position statement - Simulation-based training for obstetrics and gynaecology during the COVID-19 pandemic.

The specialty of Obstetrics and Gynaecology has been on the forefront of introducing simulation in post graduate education for the past two decades. Simulation training is known to enhance psychomotor skills and is considered an important step in the transition from classroom learning to clinical practice. Training on simulators allows trainees to acquire basic skills before getting involved in day to day care in real life situations. Clinical circumstances around the COVID 19 pandemic have highlighted the key importance of simulation training in delivering post graduate curriculum.

In Vitro Systematic Drug Testing Reveals Carboplatin, Paclitaxel, and Alpelisib as a Potential Novel Combination Treatment for Adult Granulosa Cell Tumors.

Adult granulosa cell tumors (AGCTs) arise from the estrogen-producing granulosa cells. Treatment of recurrence remains a clinical challenge, as systemic anti-hormonal treatment or chemotherapy is only effective in selected patients. We established a method to rapidly screen for drug responses in vitro using direct patient-derived cell lines in order to optimize treatment selection. The response to 11 monotherapies and 12 combination therapies, including chemotherapeutic, anti-hormonal, and targeted agents, were tested in 12 AGCT-patient-derived cell lines and an AGCT cell line (KGN). Drug screens were performed within 3 weeks after tissue collection by measurement of cell viability 72 h after drug application. The potential synergy of drug combinations was assessed. The human maximum drug plasma concentration (Cmax) and steady state (Css) thresholds obtained from available phase I/II clinical trials were used to predict potential toxicity in patients. Patient-derived AGCT cell lines demonstrated resistance to all monotherapies. All cell lines showed synergistic growth inhibition by combination treatment with carboplatin, paclitaxel, and alpelisib at a concentration needed to obtain 50% cell death (IC50) that are below the maximum achievable concentration in patients (IC50 < Cmax). We show that AGCT cell lines can be rapidly established and used for patient-specific in vitro drug testing, which may guide treatment decisions. Combination treatment with carboplatin, paclitaxel, and alpelisib was consistently effective in AGCT cell lines and should be further studied as a potential effective combination for AGCT treatment in patients.

Whole Genome Analysis of Ovarian Granulosa Cell Tumors Reveals Tumor Heterogeneity and a High-Grade TP53-Specific Subgroup.

Adult granulosa cell tumors (AGCTs) harbor a somatic FOXL2 c.402C>G mutation in ~95% of cases and are mainly surgically removed due to limited systemic treatment effect. In this study, potentially targetable genomic alterations in AGCTs were investigated by whole genome sequencing on 46 tumor samples and matched normal DNA. Copy number variant (CNV) analysis confirmed gain of chromosome 12 and 14, and loss of 22. Pathogenic TP53 mutations were identified in three patients with highest tumor mutational burden and mitotic activity, defining a high-grade AGCT subgroup. Within-patient tumor comparisons showed 29-80% unique somatic mutations per sample, suggesting tumor heterogeneity. A higher mutational burden was found in recurrent tumors, as compared to primary AGCTs. FOXL2-wildtype AGCTs harbored DICER1, TERT(C228T) and TP53 mutations and similar CNV profiles as FOXL2-mutant tumors. Our study confirms that absence of the FOXL2 c.402C>G mutation does not exclude AGCT diagnosis. The lack of overlapping variants in targetable cancer genes indicates the need for personalized treatment for AGCT patients.

Robot assisted surgery during the COVID-19 pandemic, especially for gynecological cancer: a statement of the Society of European Robotic Gynaecological Surgery (SERGS).

All surgery performed in an epicenter of the coronavirus disease 2019 (COVID-19) pandemic, irrespective of the known or suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) status of the patient, should be regarded as high risk and protection of the surgical team at the bedside should be at the highest level. Robot assisted surgery (RAS) may help to reduce hospital stay for patients that urgently need complex-oncological-surgery, thus making room for COVID-19 patients. In comparison to open or conventional laparoscopic surgery, RAS potentially reduces not only contamination with body fluids and surgical gasses of the surgical area but also the number of directly exposed medical staff. A prerequisite is that general surgical precautions under COVID-19 circumstances must be taken, with the addition of prevention of gas leakage: • Use highest protection level III for bedside assistant, but level II for console surgeon. • Reduce the number of staff at the operation room. • Ensure safe and effective gas evacuation. • Reduce the intra-abdominal pressure to 8 mmHg or below. • Minimize electrocautery power and avoid use of ultrasonic sealing devices. • Surgeons should avoid contact outside theater (both in and out of the hospital).

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.

EBCOG position statement: Gender neutral HPV vaccination for young adults.

Human Papilloma Virus (HPV) has been implicated in the initiation of several types of cancers in both females and males. Therefore, it is imperative that national immunization programs should ensure that both young women and young men receive full immunization for herd immunity in their teenage years. A recent review confirmed that vaccination of boys and girls would be most cost-effective under the circumstances that both individual costs and coverage are low. By doing so, it would be possible to reduce the incidence of HPV-related malignancies to a large extent at later age in both sexes.

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.

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.

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.

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.

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.

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.

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.