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High‐risk HPV (hrHPV)‐based screening has led to many unnecessary colposcopy referrals, mainly because of direct referral after low‐grade cytology (ASC‐US/LSIL). DNA methylation and genotyping tests on ASC‐US/LSIL samples have the potential to significantly improve the efficiency of screening. In this study, 12 triage strategies were constructed from FAM19A4/miR124‐2 or ASCL1/LHX8 methylation, HPV16/18 or HPV16/18/31/33/45 genotyping and 1‐year repeat cytology. The performance was evaluated on 215 hrHPV‐positive ASC‐US/LSIL samples from the IMPROVE trial (NTR5078). Performance was measured by colposcopy referral rate, positive predictive value (PPV) for detecting precancer (CIN3), and negative predictive value (NPV). To evaluate efficiency, strategies were ordered by the cumulative colposcopy referral rate after 1‐year cytology and compared by the marginal PPV to detect one additional CIN3 (mPPV). The most conservative strategy (referral when HPV16/18 and FAM19A4/miR124 methylation results are positive) had a direct referral rate of 5.2%, a cumulative referral rate after 1‐year cytology of 54.1%, and mPPV of 19.3%. Replacing HPV16/18 by HPV16/18/31/33/45 increased the cumulative 1‐year referral rate to 54.6%, and yielded an mPPV of 10.0%. Similar results were obtained for strategies with ASCL1/LHX8 methylation. Of all strategies, referral after an HPV16/18/31/33/45 positive, ASCL1/LHX8 methylation‐positive, and/or 1‐year cytology‐positive result yielded the highest direct and cumulative 1‐year colposcopy referral rates of 64.4% and 79.1%, respectively. The NPVs after 1‐year cytology varied between 98.1% and 99.4%, warranting a return to routine screening. Altogether, DNA methylation‐based triage strategies are recommended as they are discriminative for CIN3 and control the number of immediate colposcopy referrals. [ABSTRACT FROM AUTHOR]

Simple Summary: This study examined the cost-effectiveness of sentinel lymph node mapping versus routine pelvic lymphadenectomy for assessing lymph nodes in patients with high-risk endometrial cancer. Using a decision analytic model, we compared the two methods based on costs and health outcomes. We found that sentinel lymph node mapping was more effective and less expensive than lymphadenectomy. The cost savings and improved outcomes primarily stemmed from the fewer side effects associated with sentinel lymph node mapping. The analysis confirmed that sentinel lymph node mapping is the best option for determining the need for additional treatment in these patients. Overall, this study suggests that sentinel lymph node mapping should be the preferred method for lymph node assessment in people with high-risk endometrial cancer. Objectives. The aim was to evaluate the cost-effectiveness of sentinel lymph node (SLN) mapping in comparison to routine pelvic lymphadenectomy for lymph node assessment in patients with high-risk endometrial cancer (EC). Methods. A decision–analytic model was developed to compare SLN mapping with pelvic lymphadenectomy for guiding adjuvant therapy in patients with high-risk endometrioid and non-endometrioid EC, focusing on costs and health outcomes. The input data were obtained from systematic literature searches and expert consensus. Quality-adjusted life years (QALYs) was utilized as the measure of effectiveness. The model was constructed from a healthcare perspective, and the impact of uncertainty was evaluated through sensitivity analyses. Results. The base case analysis indicated that sentinel lymph node mapping is the dominant strategy for lymph node assessment in patients with high-risk endometrial cancer, as it was found to be both more effective and less costly than lymphadenectomy. The improved outcomes and reduced costs associated with SLN mapping primarily result from a decrease in the side effects related to lymph node assessment. Sensitivity analyses demonstrated that the outcome of the model was robust to variations in input values. Conclusion. SLN mapping is the most cost-effective strategy to determine the need for adjuvant therapy in patients with high-risk endometrioid and non-endometrioid endometrial cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian cancer is difficult to treat because there are several subtypes that differ on the cell level and in their physical characteristics. Cells in the laboratory are used to test the success of a treatment before introducing it in clinical practice. However, these cell line models often fail to accurately represent real-life ovarian cancer tumors. Cells contain a communication network with ''chains" called signal transduction pathways. These pathways control the cell's behavior. Aberrant activity in these pathways can cause disbalance in cell's processes, like cell multiplication and cell death. Ovarian cancer could be represented more accurately by mirroring its behavior through pathway activity. We identified 12 cell lines that had similar pathways compared to an actual patient's ovarian cancer tissue samples. This could improve the development of promising new treatments that are more effective in patients, making research results more reliable and potentially benefiting future ovarian cancer therapies. Background/Objectives: Advances in treatment options have barely improved the prognosis of ovarian carcinoma (OC) in recent decades. The inherent heterogeneity of OC underlies challenges in treatment (development) and patient stratification. One hurdle for effective drug development is the lack of patient-representative disease models available for preclinical drug research. Based on quantitative measurement of signal transduction pathway (STP) activity in cell lines, we aimed to identify cell line models that better mirror the different clinical subtypes of OC. Methods: The activity of seven oncogenic STPs (signal transduction pathways) was determined by previously described STP technology using transcriptome data from untreated OC cell lines available in the GEO database. Hierarchal clustering of cell lines was performed based on STP profiles. Associations between cell line histology (original tumor), cluster, and STP profiles were analyzed. Subsequently, STP profiles of clinical OC tissue samples were matched with OC cell lines. Results: Cell line search resulted in 80 cell line transcriptome data from 23 GEO datasets, with 51 unique cell lines. These cell lines were derived from eight different histological OC subtypes (as determined for the primary tumor). Clustering revealed seven clusters with unique STP profiles. When borderline tumors (n = 6), high-grade serous (n = 51) and low-grade (n = 31) OC were matched with cell lines, twelve different cell lines were identified as potentially patient-representative OC cell line models. Conclusions: Based on STP activity, we identified twelve different cell lines that were the most representative of the common subtypes of OC. These findings are important to improve drug development for OC. [ABSTRACT FROM AUTHOR]

Author(s): Diede L. Loopik 1,*, Joris van Drongelen 2, Ruud L. M. Bekkers 3, Quirinus J. M. Voorham 4, Willem J. G. Melchers 5, Leon F. A. G. Massuger 2, [...], Background Excisional procedures of cervical intraepithelial neoplasia (CIN) may increase the risk of preterm birth. It is unknown whether this increased risk is due to the excision procedure itself, to the underlying CIN, or to secondary risk factors that are associated with both preterm birth and CIN. The aim of this study is to assess the risk of spontaneous preterm birth in women with treated and untreated CIN and examine possible associations by making a distinction between the excised volume of cervical tissue and having cervical disease. Methods and findings This Dutch population-based observational cohort study identified women aged 29 to 41 years with CIN between 2005 and 2015 from the Dutch pathology registry (PALGA) and frequency matched them with a control group without any cervical abnormality based on age at and year of pathology outcome (i.e., CIN or normal cytology) and urbanization ( In total, 29,907, 5,940, and 9,412 pregnancies were included in the control, untreated CIN, and treated CIN group, respectively. The control group showed a 4.8% (1,002/20,969) proportion of spontaneous preterm birth, which increased to 6.9% (271/3,940) in the untreated CIN group, 9.5% (600/6,315) in the treated CIN group, and 15.6% (50/321) in the group with multiple treatments. Women with untreated CIN had a 1.38 times greater odds of preterm birth compared to women without CIN (95% confidence interval (CI) 1.19 to 1.60; P < 0.001). For women with treated CIN, these odds 2.07 times increased compared to the control group (95% CI 1.85 to 2.33; P < 0.001). Treated women had a 1.51 times increased odds of preterm birth compared to women with untreated CIN (95% CI 1.29 to 1.76; P < 0.001). Independent from cervical disease, a volume excised from the cervix of 0.5 to 0.9 cc increased the odds of preterm birth 2.20 times (37/379 versus 1,002/20,969; 95% CI 1.52 to 3.20; P < 0.001). These odds further increased 3.13 times and 5.93 times for women with an excised volume of 4 to 8.9 cc (90/724 versus 1,002/20,969; 95% CI 2.44 to 4.01; P < 0.001) and [greater than or equal to]9 cc (30/139 versus 1,002/20,969; 95% CI 3.86 to 9.13; P < 0.001), respectively. Limitations of the study include the retrospective nature, lack of sufficient information to calculate odds of preterm birth Conclusions In this study, we observed a strong correlation between preterm birth and a volume of [greater than or equal to]0.5 cc excised cervical tissue, regardless of the severity of CIN. Caution should be taken when performing excisional treatment in women of reproductive age as well as prudence in case of multiple biopsies. Fertile women with a history of performing multiple biopsies or excisional treatment for CIN may benefit from close surveillance during pregnancy.

Objective: Cytology performed directly on hrHPV-positive self-samples (reflex cytology) is feasible and for women with abnormal cytology, an additional cytology test at the general practitioner could be omitted. The aim of this study is to assess the added value of digital imaging (ThinPrep® Imaging System) on the clinical utility of reflex cytology by reducing screening error. Design: A secondary analysis of a prospective cohort study. Setting: One of five Dutch screening laboratories. Population: Women tested hrHPV-positive on self-samples between December 2018 and August 2019. Methods: Self-samples were used for reflex cytology with and without digital imaging. The follow-up data (cytological and histological results within 1 year of follow- up) were obtained through the Dutch Pathology Registry (PALGA). Main outcome measures: Test performance of the reflex cytology was determined by comparing it with physician-collected follow-up results. Results: The sensitivity for detecting abnormal cells by reflex cytology on self-samples increased significantly from 26.3% (42/160; 95% confidence interval [CI] 19.6–33.8) without digital imaging to 35.4% (56/158; 95% CI 28–43.4) with digital imaging (P < 0.05) without compromising specificity. Importantly, 41.7% of women with ≥CIN2 (35/84) and 45.6% with ≥CIN3 (26/57) were detected by reflex cytology with digital imaging on hrHPV-positive self-samples. Conclusion: Digital imaging is of added value to reflex cytology on hrHPV-positive self-samples with a 9% increase in sensitivity. If reflex cytology on self-samples analysed with digital imaging had been implemented in the screening programme, 35.4% of the hrHPV-positive women with abnormal cytology on additional physician-collected samples could have been referred directly for colposcopy. [ABSTRACT FROM AUTHOR]

Simple Summary: Sentinel lymph node (SLN) mapping is safe, feasible, and cost-effective to determine the lymph node status in endometrial cancer (EC). The aim of our prospective SLIM study was to investigate the incidence of SLN metastases and the contribution of SLN mapping in the management of presumed low- and intermediate-risk EC, i.e., clinical early-stage EC, endometrioid histology, grade 1 or 2. SLN metastases were present in 11.2% of 152 patients. Adjuvant management was adjusted based on the SLN status in 7.9% of patients: in 5.9% adjuvant treatment was added due to a positive sentinel node, and in 2.0% adjuvant treatment was limited due to unexpected grade 3 disease with a negative SLN. SLN mapping seems important in patients with presumed low- and intermediate-risk EC and may avoid undertreatment as well as overtreatment. The aim was to investigate the incidence of sentinel lymph node (SLN) metastases and the contribution of SLN mapping in presumed low- and intermediate-risk endometrial cancer (EC). A multicenter, prospective cohort study in presumed low- and intermediate-risk EC patients was performed. Patients underwent SLN mapping using cervical injections of indocyanine green and a minimally invasive hysterectomy with bilateral salpingo-oophorectomy. The primary outcome was the incidence of SLN metastases, leading to adjusted adjuvant treatment. Secondary outcomes were the SLN detection rate and the occurrence of complications. Descriptive statistics and univariate general linear model analyses were used. A total of 152 patients were enrolled, with overall and bilateral SLN detection rates of 91% and 61%, respectively. At final histology, 78.9% of patients (n = 120) had truly low- and intermediate-risk EC. Macro- and micro-metastases were present in 11.2% (n = 17/152), and three patients had isolated tumor cells (2.0%). Nine patients (5.9%) had addition of adjuvant radiotherapy based on SLN metastases only. In 2.0% of patients with high-risk disease, adjuvant therapy was more limited due to negative SLNs. This study emphasizes the importance of SLN mapping in presumed early-stage, grade 1 and 2 EC, leading to individualized adjuvant management, resulting in less undertreatment and overtreatment. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to assess the SLN detection rate in presumed early stage, low- and intermediate-risk endometrial cancers, the incidence of SLN metastases, and the negative predictive value of SLN mapping performed with indocyanine green (ICG). Methods: A systematic review with meta-analyses was conducted. Study inclusion criteria were A) low- and intermediate-risk endometrial cancer, B) the use of ICG per cervical injection; C) a minimum of twenty included patients per study. To assess the negative predictive value of SLN mapping, D) a subsequent lymphadenectomy was an additional inclusion criterion. Results: Fourteen studies were selected, involving 2,117 patients. The overall and bilateral SLN detection rates were 95.6% (95% confidence interval [CI]=92.4%-97.9%) and 76.5% (95% CI=68.1%-84.0%), respectively. The incidence of SLN metastases was 9.6% (95% CI=5.1%-15.2%) in patients with grade 1-2 endometrial cancer and 11.8% (95% CI=8.1%-16.1%) in patients with grade 1-3 endometrial cancer. The negative predictive value of SLN mapping was 100% (95% CI=98.8%-100%) in studies that included grade 1-2 endometrial cancer and 99.2% (95% CI=97.9%-99.9%) in studies that also included grade 3. Conclusion: SLN mapping with ICG is feasible with a high detection rate and negative predictive value in low- and intermediate-risk endometrial cancers. Given the incidence of SLN metastases is approximately 10% in those patients, SLN mapping may lead to stage shifting with potential therapeutic consequences. Given the high negative predictive value with SLN mapping, routine lymphadenectomy should be omitted in low- and intermediaterisk endometrial cancer. [ABSTRACT FROM AUTHOR]