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Natural killer (NK) cell therapy represents an attractive immunotherapy approach against recurrent epithelial ovarian cancer (EOC), as EOC is sensitive to NK cell-mediated cytotoxicity. However, NK cell antitumor activity is dampened by suppressive factors in EOC patient ascites. Here, we integrated functional assays, soluble factor analysis, high-dimensional flow cytometry cellular component data and clinical parameters of advanced EOC patients to study the mechanisms of ascites-induced inhibition of NK cells. Using a suppression assay, we found that ascites from EOC patients strongly inhibits peripheral blood-derived NK cells and CD34+ progenitor-derived NK cells, albeit the latter were more resistant. Interestingly, we found that higher ascites-induced NK cell inhibition correlated with reduced progression-free and overall survival in EOC patients. Furthermore, we identified transforming growth factor (TGF)-β1 to correlate with ascites-induced NK cell dysfunction and reduced patient survival. In functional assays, we showed that proliferation and anti-tumor reactivity of CD34+ progenitor-derived NK cells are significantly affected by TGF-β1 exposure. Moreover, inhibition of TGF-β1 signaling with galunisertib partly restored NK cell functionality in some donors. For the cellular components, we showed that the secretome is associated with a different composition of CD45+ cells between ascites of EOC and benign reference samples with higher proportions of macrophages in the EOC patient samples. Furthermore, we revealed that higher TGF-β1 levels are associated with the presence of M2-like macrophages, B cell populations and T-regulatory cells in EOC patient ascites. These findings reveal that targeting TGF-β1 signaling could increase NK cell immune responses in high-grade EOC patients.

Abstract 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. Graphical Abstract

Abstract Background Currently, a PET-CT is used to assess the need for extended field radiotherapy of para-aortic lymph nodes (PALN) in International Federation of Gynaecology and Obstetrics (FIGO) stage IB2, IIA2–IVA (locally advanced stage) cervical cancer. A small study established a sensitivity and specificity estimate for PALN metastases of 50% (95% CI; 7–93%) and 83% (95% CI; 52–98%), respectively. Surgical staging of PALN may lead to a higher diagnostic accuracy. However, surgical staging of para-aortic lymph nodes in locally advanced stage cervical cancer is not common practice. Therefore, a phase 2 randomised controlled trial is needed to assess its safety and feasibility. Methods/design In addition to standard imaging (MRI or CT scan) with PET-CT, 30 adult women with FIGO stage IB2, IIA2–IVA cervical cancer will be randomised to receive either surgical staging or usual PET-CT staging. Administering extended field radiotherapy will be based on lymphadenectomy results for the intervention group and on the PET-CT results for the control group. Follow-up visits at 0, 3, 6, 9 and 12 months will assess health-related quality of life and progression-free survival. Primary safety and feasibility outcomes of surgical staging will be assessed by calculating means with 95% confidence intervals for duration of surgery, number of complications, blood loss, nodal yield after para-aortic lymphadenectomy and treatment delay due to surgical staging. Secondary patient-centred outcomes on quality of life and first year survival will be documented and compared between the two groups. Estimates of sensitivity, specificity and negative and positive predictive values of MRI, PET-CT and surgical staging will be presented with 95% CI.. All analysis will be performed according to the intention to treat principle. Discussion This study will assess safety and feasibility, expressed as the number and severity of complications, effect on quality of life and the treatment delay due to surgically staging para-aortic lymph nodes in locally advanced cervical cancer. It will provide insight in the diagnostic accuracy of the PET-CT and detection rate of missed (micro)metastases due to surgical staging. This information will be used to assess the necessity for a phase 3 study on the diagnostic accuracy of the PET-CT and surgical staging. If a phase 3 study is deemed necessary, current data can be used for sample size calculation of such a phase 3 study. Trial registration Nederlands Trial Register/Dutch Trial Registry ( www.trialregister.nl ), NTR4922. Registered on 24 November 2014.

Abstract Background Data on health-related quality of life (HRQoL) is paramount for shared and evidence based decision-making. Since an overview of cervical cancer HRQoL tools and their validity appears to be lacking, we performed a systematic review on usage of disease specific HRQoL instruments in cervical cancer patients and their psychometric properties to identify the most suitable cervical cancer specific HRQoL tool. Methods We searched Pubmed, EMBASE and PsycINFO from inception up to 18 October 2016 for studies on quality of life in cervical cancer patients. Data extraction and HRQoL identification was performed by two independent reviewers. Validation studies of the identified cervical cancer specific HRQoL tools were retrieved and assessed on psychometric properties using the COSMIN checklist. All used cervical cancer specific HRQoL instruments were scored and ranked according to their psychometric properties. Results We included 156 studies (20,690 patients) and identified 31 HRQoL tools. The EORTC QLQ-CX24 (35 studies; 5,556 patients) and FACT-Cx (22 studies; 4,224 patients) were the only cervical cancer specific tools. The EORTC QLQ-CX24 had 4 out of 9 positive rated psychometric properties; internal consistency, content and construct validity, and agreement. Criterion validity, reliability, and interpretability scored doubtful. Responsiveness and floor- and ceiling effects were not reported. The FACT-Cx had 2 out of 9 positive rated psychometric properties; internal consistency and agreement. Content validity, reliability, and interpretability scored doubtful while criterion and construct validity scored negative. Responsiveness and floor- and ceiling effects were not reported. Conclusion The validity of the often used EORTC QLQ-CX24 questionnaire for cervical cancer patients remains uncertain as 5 out of 9 psychometric properties were doubtful or not reported in current literature. Cervical cancer specific HRQoL tools should therefore always be used in conjunction with validated generic cancer HRQoL tools until proper validity has been proven, or a more valid tool has been developed.

Ascites is a prominent feature of ovarian cancer and could serve as liquid biopsy to assess the immune status of patients. Tumor-infiltrating T lymphocytes are correlated with improved survival in ovarian cancer. To investigate whether immune cells in ascites are associated with patient outcome, we analyzed the amount of dendritic cell (DC) and T cell subsets in ascites from ovarian cancer patients diagnosed with high-grade serous cancer (HGSC). Ascites was collected from 62 HGSC patients prior to chemotherapy. Clinicopathological, histological and follow-up data from patients were collected. Ascites-derived immune cells were isolated using density-gradient centrifugation. The presence of myeloid DCs (BDCA-1+, BDCA-3+, CD16+), pDCs (CD123+BDCA-2+), and T cells (CD4+, CD8+) was analyzed using flow cytometry. Complete cytoreduction, response to primary treatment and chemosensitivity were associated with improved patient outcome. In contrast, immune cells in ascites did not significantly correlate with patient survival. However, we observed a trend toward improved outcome for patients having low percentages of CD4+ T cells. Furthermore, we assessed the expression of co-stimulatory and co-inhibitory molecules on T cells and non-immune cells in 10 ascites samples. PD-1 was expressed by 30% of ascites-derived T cells and PD-L1 by 50% of non-immune cells. However, the percentage of DC and T cell subsets in ascites was not directly correlated to the survival of HGSC patients.

The underlying causes of labor dystocia can be various. Lack of expulsive forces or fetal malpresentation are amongst the most common ones. However, pelvic masses are described as well. Here we describe two cases of labor dystocia as first presentation of pelvic malignancy.

Objectives To develop an interactive tool that estimates what potential benefits are needed for the robot to provide value for money when compared with endoscopic or open surgical interventions.Design A generic online interactive tool was developed to analyze the (health) effects needed to compensate for the additional costs of using a surgical robotic system from a healthcare perspective. The application of the tool is illustrated with a hypothetical new surgical robotic platform. A synthesis of evidence from different sources was used combined with interviews with surgeons.Setting Flexible tool that can be adapted to flexible settings.Participants Any hospital patient group for which robotic, endoscopic or open surgical procedures may be considered as appropriate treatment alternatives (eg, urology, gynecology, and so on).Intervention Robotically assisted surgical interventions.Comparator Endoscopic or open surgical interventions.Main outcome measures Thresholds of how much (health) effect is needed for robot-assisted surgery to provide value for money and to become cost-effective.Results The utilization rate of the surgical robotic system and a reduction in complications appeared to be important aspects in determining the value for money. To become cost-effective, it was deemed important for new surgical robotic systems to have added clinical benefit and become less costly than the current system.Conclusions This paper and its assisting interactive tool can be used by clinicians, researchers, and policymakers to gain insight in the benefit needed to provide value for money when using a (new) surgical robotic system or, when the effects are known or can be estimated, to assess the value for money for a specific indication. For robotic surgery to provide most value for money, we recommend assessing for each indication whether the necessary effects seem achievable.