Optimising follow-up strategy based on cytology and human papillomavirus after fertility-sparing surgery for early stage cervical cancer: a nationwide, population-based, retrospective cohort study.

BACKGROUND: The optimal follow-up strategy to detect recurrence after fertility-sparing surgery for early stage cervical cancer is unknown. Tailored surveillance based on individual risks could contribute to improved efficiency and, subsequently, reduce costs in health care. The aim of this study was to establish the predictive value of cervical cytology and high-risk human papillomavirus (HPV) testing to detect recurrent cervical intraepithelial neoplasia grade 2 or worse (CIN2+; including recurrent cervical cancer) after fertility-sparing surgery. METHODS: In this nationwide, population-based, retrospective cohort study, we used data from the Netherlands Cancer Registry and the Dutch Nationwide Pathology Databank. All patients aged 18-40 years with cervical cancer of any histology who received fertility-sparing surgery (ie, large loop excision of the transformation zone, conisation, or trachelectomy) between Jan 1, 2000, and Dec 31, 2020, were included. Pathology data from diagnosis, treatment, and during follow-up were analysed. The primary and secondary outcomes were the cumulative incidence of recurrent CIN2+ and recurrence-free survival, overall and stratified by results for cytology and high-risk HPV. FINDINGS: 1548 patients were identified, of whom 1462 met the inclusion criteria. Of these included patients, 19 568 pathology reports were available. The median age at diagnosis was 31 years (IQR 30-35). After a median follow-up of 6·1 years (IQR 3·3-10·8), recurrent CIN2+ was diagnosed in 128 patients (cumulative incidence 15·0%, 95% CI 11·5-18·2), including 52 patients (cumulative incidence 5·4%, 95% CI 3·7-7·0) with recurrent cervical cancer. The overall 10-year recurrence-free survival for CIN2+ was 89·3% (95% CI 87·4-91·3). By cytology at first follow-up visit within 12 months after fertility-sparing surgery, 10-year recurrence-free survival for CIN2+ was 92·1% (90·2-94·1) in patients with normal cytology, 84·6% (77·4-92·3) in those with low-grade cytology, and 43·1% (26·4-70·2) in those with high-grade cytology. By high-risk HPV status at first follow-up visit within 12 months after surgery, 10-year recurrence-free survival for CIN2+ was 91·1% (85·3-97·3) in patients who were negative for high-risk HPV and 73·6% (58·4-92·8) in those who were positive for high-risk HPV. Cumulative incidence of recurrent CIN2+ within 6 months after any follow-up visit (6-24 months) in patients negative for high-risk HPV with normal or low-grade cytology was 0·0-0·7% and with high-grade cytology was 0·0-33·3%. Cumulative incidence of recurrence in patients positive for high-risk HPV with normal or low-grade cytology were 0·0-15·4% and with high-grade cytology were 50·0-100·0%. None of the patients who were negative for high-risk HPV without high-grade cytology, at 6 months and 12 months, developed recurrence. INTERPRETATION: Patients who are negative for high-risk HPV with normal or low-grade cytology at 6-24 months after fertility-sparing surgery, could be offered a prolonged follow-up interval of 6 months. This group comprises 80% of all patients receiving fertility-sparing surgery. An interval of 12 months seems to be safe after two consecutive negative tests for high-risk HPV with an absence of high-grade cytology, which accounts for nearly 75% of all patients who receive fertility-sparing surgery. FUNDING: KWF Dutch Cancer Society.

DNA methylation testing for endometrial cancer detection in urine, cervicovaginal self-samples and cervical scrapes.

Endometrial cancer incidence is rising and current diagnostics often require invasive biopsy procedures. DNA methylation marker analysis of minimally- and non-invasive sample types could provide an easy-to-apply and patient-friendly alternative to determine cancer risk. Here, we compared the performance of DNA methylation markers to detect endometrial cancer in urine, cervicovaginal self-samples and clinician-taken cervical scrapes. Paired samples were collected from 103 patients diagnosed with stage I to IV endometrial cancer. Urine and self-samples were collected at home. All samples were tested for nine DNA methylation markers using quantitative methylation-specific PCR. Methylation levels measured in endometrial cancer patients were compared to unpaired samples of 317 healthy controls. Diagnostic performances were evaluated by univariable and multivariable logistic regression analysis, followed by leave-one-out cross-validation. Each methylation marker showed significantly higher methylation levels in all sample types of endometrial cancer patients compared to healthy controls (P < .01). Optimal three-marker combinations demonstrated excellent diagnostic performances with area under the receiver operating curve values of 0.95 (95% CI: 0.92-0.98), 0.94 (0.90-0.97) and 0.97 (0.96-0.99), for endometrial cancer detection in urine, self-samples and scrapes, respectively. Sensitivities ranged from 89% to 93% at specificities of 90% to 92%. Virtually equal performances were obtained after cross-validation and excellent diagnostic performances were maintained for stage I endometrial cancer detection. Our study shows the value of methylation analysis in patient-friendly sample types for endometrial cancer detection of all stages. This approach has great potential to screen patient populations at risk for endometrial cancer.

European multidisciplinary tumor boards support cross-border networking and increase treatment options for patients with rare gynecological tumors.

OBJECTIVE: To evaluate outcomes of European cross-border multidisciplinary tumor boards in terms of participation, adherence to treatment recommendations, and access to novel treatment strategies. METHODS: The European reference network for rare gynecological tumors (EURACAN G2 domain) aims to improve the diagnosis, management, and treatment of patients with these cancers. Cross-border multidisciplinary tumor boards were initiated to facilitate intercollegiate clinical discussions across Europe and increase patients' access to specialist treatment recommendations and clinical trials. All G2 healthcare providers were invited to participate in monthly multidisciplinary meetings. Patient data were collected using a standardized form and case summaries were distributed before each meeting. After each tumor board, a meeting summary with treatment recommendations was sent to all participants and the project manager at the coordinating center. The multidisciplinary tumor board format and outcomes were regularly discussed at G2 domain meetings. Anonymized clinical data and treatment recommendations were registered in a prospective database. For this report, clinical data were collected between November 2017 and December 2020 and follow-up data retrieved until May 2021. RESULTS: During the 3-year period, 31 multidisciplinary tumor boards were held with participants from 10 countries and 20 centers. 91 individual patients were discussed between one and six times for a total of 109 case discussions. Follow-up data were retrieved from 64 patients and 80 case discussions. Adherence to treatment recommendations was 99%. Multidisciplinary tumor board recommendations resulted in 11 patients getting access to off-label treatment and one patient being enrolled in a clinical trial in another European country. 14/91 patients were recommended for surveillance only when additional treatment had been considered locally. CONCLUSION: Cross-border multidisciplinary tumor boards enable networking and clinical collaboration between healthcare professionals in different countries. Surveillance strategies, off-label drug use, and increased participation in clinical trials are possible benefits to patients with rare gynecological tumors.

Surgical Management of Gestational Trophoblastic Disease.

Background Gestational Trophoblastic Disease (GTD) is a rare pregnancy related condition consisting of premalignant and malignant forms arising from proliferation of trophoblastic cells. The malignant forms are collectively referred to as Gestational Trophoblastic Neoplasia (GTN) and are highly sensitive to chemotherapy. However, surgical procedures remain indispensable in the diagnosis and treatment of GTD. Objectives The aim of this review is to summarize surgical interventions in the treatment of GTD and GTN. We reviewed indications, efficacy, possible complications and oncological outcomes of surgery. Methods Three searches were performed in the databases of PubMed, Embase and the Cochrane Library to create an up-to-date overview of existing literature on the following subjects: 1. The role of primary hysterectomy in GTD and GTN 2. The role of second curettage in GTD and GTN 3. Fertility sparing surgery in GTN 4. Surgical management of metastases. Included articles originated from the time period 1952-2022. Articles written in English, Spanish and French were included. Outcomes Thirty-eight articles were found and selected. Surgical evacuation through suction curettage is most used and advised in the treatment of GTD. A second curettage could be beneficial in patients with low hCG levels and low FIGO scores. In women who have completed their families, primary hysterectomy might be considered as the risk of subsequent GTN is lower than after suction curettage. In case of the rare forms of GTN (Epithelioid Trophoblastic Tumor (ETT) or Placental Site Trophoblastic Tumor (PSTT)) surgical tumor resection remains the most important step in treatment. Data on fertility sparing surgery in GTN are scarce and this treatment should be considered experimental. Conclusion and Outlook Surgery remains an important part of treatment of GTD and is sometimes indispensable to achieve curation. Further collection of evidence is needed to determine treatment steps.

Effects of chemotherapy on ovaries of pregnant mice.

PURPOSE: It is unknown if future fertility is compromised by the administration of chemotherapy during pregnancy. The aim of this study was to identify if chemotherapy affects the maternal ovaries during pregnancy and whether these effects depend on type of chemotherapy and duration of exposure. METHODS: Pregnant 8-week-old female BL6 mice were exposed to 6 different single chemotherapeutic agents (carboplatin, cisplatin, paclitaxel, epirubicin, doxorubicin, or cyclophosphamide) or saline at gestational day (GD) 13.5. The mice were sacrificed at GD 15.5 or GD 18.5. Ovaries were assessed by histopathology and immunohistochemistry. Follicle count was determined per follicle stage and per treatment modality. RESULTS: Maternal ovarian damage was demonstrated by the presence of apoptosis and necrosis in preantral follicles. The extent of this damage depends upon type of chemotherapy and duration of exposure (2 or 5 days). After short exposure, 81% of ovaries showed histopathologic signs of damage compared to 36% after long exposure, which might suggest a transient effect. Loss of primordial follicles (PMFs) was observed after both short and long exposure, with a reduction of more than 70%. Evidence of DNA damage, as demonstrated by phospho-H2AX expression, was present in 23% (range 0-89%) of PMFs exposed to chemotherapy, but only in the short exposure group. Overall, the least damage was seen after administration of paclitaxel. CONCLUSION: Despite physiological ovarian function suppression during gestation, chemotherapy-induced damage of the ovaries occurs in pregnant mouse models, potentially affecting future fertility.

Is less more in the surgical treatment of early-stage cervical cancer?

PURPOSE OF REVIEW: This article discusses recent developments towards less radical surgical treatment for early-stage cervical cancer. RECENT FINDINGS: Surgery is the standard treatment for early-stage cervical cancer. In the last decades, new treatment strategies have been developed aiming to reduce morbidity, without hampering oncological safety. We provide an update of the latest knowledge on safety and morbidity following less radical surgical procedures in early-stage cervical cancer. In cervical cancer with a tumour size of 2 cm or less, radical surgery (simple hysterectomy or fertility-sparing conisation) may be a well tolerated option. For patients with larger lesions (>2 cm) and wishing to preserve fertility, administration of neoadjuvant chemotherapy followed by less extensive surgery appears to be a feasible and well tolerated alternative to abdominal trachelectomy. With regard to lymph node assessment, increasing evidence shows the feasibility of the sentinel lymph node procedure instead of full pelvic lymphadenectomy. Prospective trials reporting on oncological safety are awaited.It is important to exercise caution when new surgical strategies are introduced. Despite promising retrospective data, prospective randomized studies may present unexpected results, for instance, minimally invasive radical hysterectomy showed inferior results compared to laparotomy. SUMMARY: There is a shift towards less radical treatment for early-stage cervical cancer. This review explores whether and when less is really more.

Treatment of bulky lymph nodes in locally advanced cervical cancer: boosting versus debulking.

OBJECTIVE: Treatment strategies for bulky lymph nodes in patients with locally advanced cervical cancer scheduled for definitive chemoradiation include nodal boosting with radiotherapy, surgical debulking, or both. The aim of this retrospective cohort study was to compare survival and toxicity in patients receiving these treatments and to compare them with a group that received neither form of treatment. METHODS: Women diagnosed between January 2009 and January 2017 with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB2, IIA2-IVA cervical cancer with lymph nodes ≥1.5 cm without upper limit on pretreatment imaging and treated with definitive chemoradiation were selected from the Netherlands Cancer Registry. Patients were categorized by intention-to-treat strategy: boosting, debulking, or neither treatment, with subgroup analysis for patients receiving both treatments, that is, debulking with boosting. Overall and relapse-free survival outcomes were compared by Kaplan-Meier and Cox regression analyses and toxicity by logistic regression analysis. RESULTS: Of 190 patients, 101 (53%) received only nodal boosting, 31 (16%) debulking alone, 29 (15%) debulking combined with boosting, and 29 (15%) received neither treatment. The 5 year overall and relapse-free survival for the treatment groups were 58%, 45% and 45% (p=0.19), and 47%, 44% and 46% (p=0.87), respectively. Multivariable Cox regression analyses demonstrated no differences in overall and relapse-free survival. Combination of debulking with boosting was associated with decreased overall and relapse-free survival compared with debulking alone (HR 2.47, 95% CI 1.22 to 5.00; and HR 2.37, 95% CI 1.14 to 4.93). Nodal boosting was independently associated with a decreased toxicity risk compared with debulking strategy (OR 0.37, 95% CI 0.16 to 0.83). CONCLUSIONS: This study showed no survival benefit from either nodal boosting or debulking strategy in patients with suspicious bulky nodes. Nodal boosting might, however, be associated with less toxicity. Dual treatment with debulking and boosting showed a worse survival outcome because this group probably represents patients with poor prognostic factors.

Classification of high-grade cervical intraepithelial neoplasia by p16ink4a , Ki-67, HPV E4 and FAM19A4/miR124-2 methylation status demonstrates considerable heterogeneity with potential consequences for management.

High-grade cervical intraepithelial neoplasia (CIN2 and CIN3) represents a heterogeneous disease with varying cancer progression risks. Biomarkers indicative for a productive human papillomavirus (HPV) infection (HPV E4) and a transforming HPV infection (p16ink4a , Ki-67 and host-cell DNA methylation) could provide guidance for clinical management in women with high-grade CIN. This study evaluates the cumulative score of immunohistochemical expression of p16ink4a (Scores 0-3) and Ki-67 (Scores 0-3), referred to as the "immunoscore" (IS), in 262 CIN2 and 235 CIN3 lesions derived from five European cohorts in relation to immunohistochemical HPV E4 expression and FAM19A4/miR124-2 methylation in the corresponding cervical scrape. The immunoscore classification resulted in 30 lesions within IS group 0-2 (6.0%), 151 lesions within IS group 3-4 (30.4%) and 316 lesions within IS group 5-6 (63.6%). E4 expression decreased significantly from CIN2 to CIN3 (P < .001) and with increasing immunoscore group (Ptrend < .001). Methylation positivity increased significantly from CIN2 to CIN3 (P < .001) and with increasing immunoscore group (Ptrend < .001). E4 expression was present in 9.8% of CIN3 (23/235) and in 12.0% of IS group 5-6 (38/316). Notably, in a minority (43/497, 8.7%) of high-grade lesions, characteristics of both transforming HPV infection (DNA hypermethylation) and productive HPV infection (E4 expression) were found simultaneously. Next, we stratified all high-grade CIN lesions, based on the presumed cancer progression risk of the biomarkers used, into biomarker profiles. These biomarker profiles, including immunoscore and methylation status, could help the clinician in the decision for immediate treatment or a "wait and see" policy to reduce overtreatment of high-grade CIN lesions.

Ten steps to establish a national centre for gestational trophoblastic disease.

PURPOSE OF REVIEW: Gestational trophoblastic disease (GTD) is a group of heterogeneous disorders characterized by abnormal proliferation of trophoblastic tissue. GTD is a rare disease that is curable in the vast majority of patients when managed appropriately. The aim of the review is to discuss the important steps necessary to establish a center of excellence for GTD. RECENT FINDINGS: Care of patients with a rare disease is complicated by lack of strong evidence, scattering of patients across the country and limited expertise of medical professionals. The establishment of a center of excellence requires awareness of its benefit, funding, a solid business case and most of all dedicated clinicians. A multidisciplinary team and formulation of national guidelines are important steps before clinical pathways can be developed and treatment can be evaluated for improvement of care and research purposes. International embedding can facilitate the process and lead to the development of a (inter) national acknowledged sustainable center of excellence. SUMMARY: Centers of excellence could optimize the care of patients with GTD and promote research.

Noninvasive, in vivo assessment of the cervical microcirculation using incident dark field imaging.

AIM: This study evaluates the feasibility of handheld vital microscopy for noninvasive, objective assessment of the microcirculation of the human uterine cervix. We qualitatively and quantitatively describe the microcirculation in healthy subjects in order to provide a basis for its application in cervical pathology. METHODS: Incident dark field imaging was used to image the microcirculation in four quadrants of the uterine ectocervix in ten healthy participants. If the squamocolumnar junction was visible, measurements were repeated on the endocervical columnar epithelium as well. Image acquisition time was recorded and participants scored the experienced level of discomfort. Angioarchitecture was classified according to Weber's classification. Quantitative parameters included capillary density (CD), total and perfused vessel density (TVD, PVD), proportion of perfused vessels (PPV) and microvascular flow index (MFI). RESULTS: Image acquisition was easy, fast and well tolerated. Angioarchitecture was characterized by two distinctive and organized patterns; capillary loops underneath the squamous epithelium of the ectocervix and vascular networks underneath the columnar epithelium. In the image sequences containing capillary loops, mean CD was 33.2 cpll/mm2 (95% CI 28.2-38.2 cpll/mm2). In the image sequences with vascular networks, mean TVD was 12.5 mm/mm2 (95% CI 11.2-13.77 mm/mm2), mean PVD was 12.2 (95% CI 11.0-13.5 mm/mm2), MFI was 3 and PPV was 100%. CONCLUSIONS: Incident dark field imaging allows for noninvasive, real time visualization and objective evaluation and quantification of the microcirculation of the uterine cervix. The organized vascular patterns and optimal perfusion observed in healthy subjects allow for comparison with cervical pathology, for example in patients with cervical dysplasia or cervical cancer.

Fertility and pregnancy outcome in gestational trophoblastic disease.

The aim of this review is to provide an overview of existing literature and current knowledge on fertility rates and reproductive outcomes after gestational trophoblastic disease. A systematic literature search was performed to retrieve all available studies on fertility rates and reproductive outcomes after hydatidiform mole pregnancy, low-risk gestational trophoblastic neoplasia, high- and ultra-high-risk gestational trophoblastic neoplasia, and the rare placental site trophoblastic tumor and epithelioid trophoblastic tumor forms of gestational trophoblastic neoplasia. The effects of single-agent chemotherapy, multi-agent including high-dose chemotherapy, and immunotherapy on fertility, pregnancy wish, and pregnancy outcomes were evaluated and summarized. After treatment for gestational trophoblastic neoplasia, most, but not all, women want to achieve another pregnancy. Age and extent of therapy determine if there is a risk of loss of fertility. Single-agent treatment does not affect fertility and subsequent pregnancy outcome. Miscarriage occurs more often in women who conceive within 6 months of follow-up after chemotherapy. Multi-agent chemotherapy hastens the natural menopause by three years and commonly induces a temporary amenorrhea, but in young women rarely causes permanent ovarian failure or infertility. Subsequent pregnancies have a high chance of ending with live healthy babies. In contrast, high-dose chemotherapy typically induces permanent amenorrhea, and no pregnancies have been reported after high-dose chemotherapy for gestational trophoblastic neoplasia. Immunotherapy is promising and may give better outcomes than multiple schedules of chemotherapy or even high-dose chemotherapy. The first pregnancy after immunotherapy has recently been described. Data on fertility-sparing treatment in placental site trophoblastic tumor and epithelioid trophoblastic tumor are still scarce, and this option should be offered with caution. In general, patients with gestational trophoblastic neoplasia may be reassured about their future fertility and pregnancy outcome. Detailed registration of high-risk gestational trophoblastic neoplasia is still indispensable to obtain more complete data to better inform patients in the future.

FAM19A4/miR124-2 methylation in invasive cervical cancer: A retrospective cross-sectional worldwide study.

Widespread adoption of primary human papillomavirus (HPV)-based screening has encouraged the search for a triage test which retains high sensitivity for the detection of cervical cancer and precancer, but increases specificity to avoid overtreatment. Methylation analysis of FAM19A4 and miR124-2 genes has shown promise for the triage of high-risk (hr) HPV-positive women. In our study, we assessed the consistency of FAM19A4/miR124-2 methylation analysis in the detection of cervical cancer in a series of 519 invasive cervical carcinomas (n = 314 cervical scrapes, n = 205 tissue specimens) from over 25 countries, using a quantitative methylation-specific PCR (qMSP)-based assay (QIAsure Methylation Test®). Positivity rates stratified per histotype, FIGO stage, hrHPV status, hrHPV genotype, sample type and geographical region were calculated. In total, 510 of the 519 cervical carcinomas (98.3%; 95% CI: 96.7-99.2) tested FAM19A4/miR124-2 methylation-positive. Test positivity was consistent across the different subgroups based on cervical cancer histotype, FIGO stage, hrHPV status, hrHPV genotype, sample type and geographical region. In conclusion, FAM19A4/miR124-2 methylation analysis detects nearly all cervical carcinomas, including rare histotypes and hrHPV-negative carcinomas. These results indicate that a negative FAM19A4/miR124-2 methylation assay result is likely to rule out the presence of cervical cancer.

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

INTRODUCTION: Centralization has, among other aspects, been argued to have an impact on quality of care in terms of surgical morbidity. Next, monitoring quality of care is essential in identifying areas of improvement. This nationwide cohort study was conducted to determine the rate of short-term surgical complications and to evaluate its possible predictors in women with early-stage cervical cancer. MATERIAL AND METHODS: Women diagnosed with early-stage cervical cancer, 2009 FIGO stages IB1 and IIA1, between 2015 and 2017 who underwent radical hysterectomy with pelvic lymphadenectomy in 1 of the 9 specialized medical centers in the Netherlands, were identified from the Netherlands Cancer Registry. Women were excluded if primary treatment consisted of hysterectomy without parametrial dissection or radical trachelectomy. Women in whom radical hysterectomy was aborted during the procedure, were also excluded. Occurrence of intraoperative and postoperative complications and type of complications, developing within 30 days after surgery, were prospectively registered. Multivariable logistic regression analysis was used to identify predictors of surgical complications. RESULTS: A total of 472 women were selected, of whom 166 (35%) developed surgical complications within 30 days after radical hysterectomy. The most frequent complications were urinary retention with catheterization in 73 women (15%) and excessive perioperative blood loss >1000 mL in 50 women (11%). Open surgery (odds ratio [OR] 3.42; 95% CI 1.73-6.76), chronic pulmonary disease (OR 3.14; 95% CI 1.45-6.79), vascular disease (OR 1.90; 95% CI 1.07-3.38), and medical center (OR 2.83; 95% CI 1.18-6.77) emerged as independent predictors of the occurrence of complications. Body mass index (OR 0.94; 95% CI 0.89-1.00) was found as a negative predictor of urinary retention. Open surgery (OR 36.65; 95% CI 7.10-189.12) and body mass index (OR 1.15; 95% CI 1.08-1.22) were found to be independent predictors of excessive perioperative blood loss. CONCLUSIONS: Short-term surgical complications developed in 35% of the women after radical hysterectomy for early-stage cervical cancer in the Netherlands, a nation with centralized surgical care. Comorbidities predict surgical complications, and open surgery is associated with excessive perioperative blood loss.

Genome-wide microRNA analysis of HPV-positive self-samples yields novel triage markers for early detection of cervical cancer.

Offering self-sampling for HPV testing improves the effectiveness of current cervical screening programs by increasing population coverage. Molecular markers directly applicable on self-samples are needed to stratify HPV-positive women at risk of cervical cancer (so-called triage) and to avoid over-referral and overtreatment. Deregulated microRNAs (miRNAs) have been implicated in the development of cervical cancer, and represent potential triage markers. However, it is unknown whether deregulated miRNA expression is reflected in self-samples. Our study is the first to establish genome-wide miRNA profiles in HPV-positive self-samples to identify miRNAs that can predict the presence of CIN3 and cervical cancer in self-samples. Small RNA sequencing (sRNA-Seq) was conducted to determine genome-wide miRNA expression profiles in 74 HPV-positive self-samples of women with and without cervical precancer (CIN3). The optimal miRNA marker panel for CIN3 detection was determined by GRridge, a penalized method on logistic regression. Six miRNAs were validated by qPCR in 191 independent HPV-positive self-samples. Classification of sRNA-Seq data yielded a 9-miRNA marker panel with a combined area under the curve (AUC) of 0.89 for CIN3 detection. Validation by qPCR resulted in a combined AUC of 0.78 for CIN3+ detection. Our study shows that deregulated miRNA expression associated with CIN3 and cervical cancer development can be detected by sRNA-Seq in HPV-positive self-samples. Validation by qPCR indicates that miRNA expression analysis offers a promising novel molecular triage strategy for CIN3 and cervical cancer detection applicable to self-samples.

FIGO 2018 stage IB2 (2-4 cm) Cervical cancer treated with Neo-adjuvant chemotherapy followed by fertility Sparing Surgery (CONTESSA); Neo-Adjuvant Chemotherapy and Conservative Surgery in Cervical Cancer to Preserve Fertility (NEOCON-F). A PMHC, DGOG, GCIG/CCRN and multicenter study.

BACKGROUND: There are limited data regarding the optimal management of pre-menopausal women with cervical lesions measuring 2-4 cm who desire to preserve fertility. PRIMARY OBJECTIVES: To evaluate the feasibility of preserving fertility. STUDY HYPOTHESIS: Neo-adjuvant chemotherapy will be effective in reducing the size of the tumor and will enable fertility-sparing surgery without compromising oncologic outcome. TRIAL DESIGN: Pre-menopausal women diagnosed with stage International Federation of Gynecology and Obstetrics (FIGO) IB2, 2-4 cm cervical cancer who wish to preserve fertility will receive three cycles of platinum/paclitaxel chemotherapy. Patients with complete/partial response will undergo fertility-sparing surgery. Patients will be followed for 3 years to monitor outcome. Patients with suboptimal response (residual lesion ≥2 cm) will receive definitive radical hysterectomy and/or chemoradiation. MAJOR ELIGIBILITY CRITERIA: Patients must have histologically confirmed invasive cervical cancer, 2-4 cm lesion, by clinical examination and magnetic resonance imaging (MRI), negative node, and pre-menopausal (≤40 years old). Following three cycles of neo-adjuvant chemotherapy, patients must achieve a complete/partial response (residual lesion <2 cm). Exclusion criteria include high-risk histology, tumor extension to uterine corpus/isthmus (as per MRI), and suboptimal response/progression following neo-adjuvant chemotherapy. PRIMARY ENDPOINTS: Assess the rate of functional uterus defined as successful fertility-sparing surgery and no adjuvant therapy. SAMPLE SIZE: A total of 90 evaluable patients will be needed to complete the study. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Expected complete accrual in 2022 with presentation of results by 2025. TRIAL REGISTRATION NUMBER: Pending ethics submission.

Is there uniformity in definitions and treatment of gestational trophoblastic disease in Europe?

OBJECTIVES: Because gestational trophoblastic disease is rare, little evidence is available from randomized controlled trials on optimal treatment and follow-up. Treatment protocols vary within Europe, and even between different centers within countries. One of the goals of the European Organization for Treatment of Trophoblastic Diseases (EOTTD) is to harmonize treatment in Europe. To provide a basis for international standardization of definitions, treatment and follow-up protocols in gestational trophoblastic disease, we evaluated differences and similarities between protocols in EOTTD countries. METHODS: Members from each EOTTD country were asked to complete an online structured questionnaire comprising multiple-choice and multiple-answer questions. The following themes were discussed: incidence of gestational trophoblastic disease and gestational trophoblastic neoplasia, definitions, guidelines, classification system, treatment, recurrence, and follow-up. RESULTS: Forty-four respondents from 17 countries participated in this study. Guidelines were present in 80% of the countries and the FIGO (Fédération Internationale de Gynécologie et d'Obstétrique) staging and risk classification was often used to estimate risks. Agreement about when to start chemotherapy for post-molar gestational trophoblastic neoplasia was present among 66% of the respondents. Preferred first-line treatments in low- and high-risk gestational trophoblastic neoplasia were methotrexate (81%) and EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) (93%), respectively. The definition of human chorionic gonadotropin normalization after hydatidiform mole evacuation was two consecutive normal values for nine countries. The FIGO definition of post-molar gestational trophoblastic neoplasia based on human chorionic gonadotropin plateau or rise was agreed on by 69% of respondents, and only 69% and 74% defined low-risk and high-risk disease, respectively, using FIGO criteria. There were major differences in definitions of recurrence, chemotherapy resistance and follow-up protocols among countries, despite EOTTD consensus statements. CONCLUSIONS: This questionnaire provides a good overview of current clinical practices in different countries. Based on the survey results, it is clear that there are several gestationaltrophoblastic disease-related topics that need urgent attention within the EOTTD community to create more uniformity and to aid the development of uniform guidelines in Europe.

Molecular analysis for ovarian cancer detection in patient-friendly samples.

BACKGROUND: High ovarian cancer mortality rates motivate the development of effective and patient-friendly diagnostics. Here, we explored the potential of molecular testing in patient-friendly samples for ovarian cancer detection. METHODS: Home-collected urine, cervicovaginal self-samples, and clinician-taken cervical scrapes were prospectively collected from 54 patients diagnosed with a highly suspicious ovarian mass (benign n = 25, malignant n = 29). All samples were tested for nine methylation markers, using quantitative methylation-specific PCRs that were verified on ovarian tissue samples, and compared to non-paired patient-friendly samples of 110 age-matched healthy controls. Copy number analysis was performed on a subset of urine samples of ovarian cancer patients by shallow whole-genome sequencing. RESULTS: Three methylation markers are significantly elevated in full void urine of ovarian cancer patients as compared to healthy controls (C2CD4D, P = 0.008; CDO1, P = 0.022; MAL, P = 0.008), of which two are also discriminatory in cervical scrapes (C2CD4D, P = 0.001; CDO1, P = 0.004). When comparing benign and malignant ovarian masses, GHSR shows significantly elevated methylation levels in the urine sediment of ovarian cancer patients (P = 0.024). Other methylation markers demonstrate comparably high methylation levels in benign and malignant ovarian masses. Cervicovaginal self-samples show no elevated methylation levels in patients with ovarian masses as compared to healthy controls. Copy number changes are identified in 4 out of 23 urine samples of ovarian cancer patients. CONCLUSIONS: Our study reveals increased methylation levels of ovarian cancer-associated genes and copy number aberrations in the urine of ovarian cancer patients. Our findings support continued research into urine biomarkers for ovarian cancer detection and highlight the importance of including benign ovarian masses in future studies to develop a clinically useful test.

Ovarian cancer is often found late with limited treatment options. Currently, it is difficult to diagnose ovarian cancer correctly and no recommended early detection or screening methods exist. Our aim was to explore the use of DNA-based tests in patient-friendly samples for ovarian cancer detection. Patient-friendly samples are patient materials that can be collected from home without pain or discomfort, such as self-collected vaginal swabs and urine. Using DNA-based tests, we found that urine of women with ovarian cancer contains ovarian cancer-associated signals. Our findings encourage further development of a potential urine test for ovarian cancer detection. This approach could aid early detection and guide women with ovarian masses to appropriate specialist care.

Diagnostic accuracy of MRI, CT, and [18F]FDG-PET-CT in detecting lymph node metastases in clinically early-stage cervical cancer - a nationwide Dutch cohort study.

OBJECTIVES: Imaging is increasingly used to assess lymph node involvement in clinically early-stage cervical cancer. This retrospective study aimed to evaluate the diagnostic accuracy of MRI, CT, and [18F]FDG-PET-CT. METHODS: Women with International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage IA2-IIA cervical cancer and pretreatment imaging between 2009 and 2017 were selected from the Netherlands Cancer Registry. Patient-based and region-based (i.e. pelvic and common iliac) nodal status was extracted from radiology reports. Pathology results were considered the reference standard for calculating accuracy indices. Multiple imputation was used for missing pathology to limit verification bias risk. RESULTS: Nodal assessment was performed in 1676 patients with MRI, 926 with CT, and 379 with [18F]FDG-PET-CT, with suspicious nodes detected in 17%, 16%, and 48%, respectively. [18F]FDG-PET-CT was used to confirm MRI/CT results in 95% of patients. Pathology results were imputed for 30% of patients. [18F]FDG-PET-CT outperformed MRI and CT in detecting patient-based nodal metastases with sensitivities of 80%, 48%, and 40%, and AUCs of 0.814, 0.706, and 0.667, respectively, but not in specificity: 79%, 92%, and 92%. Region-based analyses showed similar indices in the pelvic region, but worse performance in the common iliac region with AUCs of 0.575, 0.554, and 0.517, respectively. CONCLUSIONS: [18F]FDG-PET-CT outperformed MRI and CT in detecting nodal metastases, which may be related to its use as a verification modality. However, MRI and CT had the highest specificity. As MRI is generally performed routinely to assess local and regional spread of cervical cancer, [18F]FDG-PET-CT can be used to confirm suspicious nodes. CRITICAL RELEVANCE STATEMENT: Accurate assessment of the nodal status in clinically early-stage cervical cancer is essential for tumour staging, treatment decision making and prognosis. KEY POINTS: • The accuracy of MRI, CT or [18F]FDG-PET-CT for nodal staging in early cervical cancer is a subject of discussion. • Overall, [18F]FDG-PET-CT outperformed MRI, followed by CT, when used as a verification modality. • Staging with MRI and the addition of [18F]FDG-PET-CT to verify high-risk cases seems to be a good approach.

Long-term outcome of placental site trophoblastic tumor in The Netherlands.

OBJECTIVE: To evaluate the outcome of 16 cases of placental site trophoblastic tumors (PSTTs) treated throughout The Netherlands. STUDY DESIGN: Patients with PSTT between 1991 and 2009 were identified using the nationwide network and registry of histopathology and cytopathology in The Netherlands (PALGA) and medical records. RESULTS: Data for 16 patients could be retrieved. The median age of the patients was 32 years. In 7 cases the antecedent pregnancy was a miscarriage and in 6, a term delivery. Clinical data on 3 patients could not be retrieved. Six patients were low-risk according to the International Federation of Gynecology and Obstetrics staging system. The median human chorionic gonadotropin (hCG) level was 46 IU/L, but in 4 patients the hCG level was not elevated. In the majority of patients a hysterectomy was performed, and 5 patients needed additional chemotherapy. There was only 1 recurrence and there were no fatalities. CONCLUSION: This study emphasizes the need for an international registration. No fatalities were registered. Because of the low incidence and limited experience of general gynecologists with this disease, there is a preference for centralization of all patients with PSTT regardless of their stage.

Experiences and preferences towards collecting a urine and cervicovaginal self-sample among women attending a colposcopy clinic.

The effectiveness of cervical cancer screening is hampered by low attendance rates. The collection of a urine sample is hypothesized to engage non-attenders in cervical cancer screening. The aim of this prospective cohort study was to evaluate experiences of women on urine collection and cervicovaginal self-sampling in a home-based setting and preferences for future cervical cancer screening. This study included 140 women, with a median age of 40 years, who were planned for a large loop excision of the transformation zone (LLETZ) procedure. All women collected a urine sample using conventional urine cups and a cervicovaginal self-sample prior to the LLETZ in a home-based setting. Following sample collection, women filled in a questionnaire. Results showed that the instructions of urine collection and cervicovaginal self-sampling were considered clear (95%, 95%CI: 88-98; 92%, 95%CI: 83-96, respectively). Women considered urine collection compared to cervicovaginal self-sampling to be more acceptable (p < 0.001), and to provide more reliable results (p < 0.001). The three highest reported preferred sampling methods for future cervical cancer screening were: urine collection (n = 39, 28%, 95%CI: 19-39), clinician-taken cervical scrape (n = 32, 23%, 95%CI: 15-34), and equal preference for urine collection, clinician-taken cervical scrape and cervicovaginal self-sampling (n = 30, 21%, 95%CI: 14-32). In conclusion, urine collection and cervicovaginal self-sampling are acceptable sampling methods, considered easy to collect in a home-based setting, and moreover, considered trustworthy. Although these results are promising, more research is required to determine if urine collection also lowers the barrier for non-attendees and, thereby, increases the attendance rates of cervical cancer screening.