Explore the vast range of titles available.

The objective of our study was to assess the oncological safety of uterine manipulators (UMs) in apparent early-stage (FIGO I-II 2009) endometrial cancer treated by minimally invasive surgery (MIS). Our single-center retrospective study includes patients who underwent endometrial cancer surgery for apparent early-stage disease by either laparoscopy or by robotic or laparoscopic-assisted vaginal hysterectomy from November 2012 to December 2020. Data on UMs, isolated tumor cells (ITCs), cytology, lymphovascular space invasion, free cancer cells in fallopian tubes, stage, histology and grade were collected. Primary and secondary outcomes were cancer recurrence and disease-specific death. Kaplan-Meier curves and multivariate logistic regression were used for statistical analysis. A total of 930 women with early-stage endometrial cancer were included; 789 (84.8%) had hysterectomy with a uterine manipulator and 141 (15.2%) without. A total of 88% had endometrioid histology, 71.6% were grade 1 and 95.7% had stage I disease. A higher risk of recurrence was observed with the Hohl manipulator (HR: 2.83. 95% CI: 1.004-7.98 = 0.0492) on univariate analysis. On multivariate analysis, neither UM was associated with recurrence. With a mean follow-up of 48 months (range 3-118), no effect was seen on disease-specific death in either Hohl or V-Care (HR: 1.66. 95% CI: 0.48-5.70 and HR:1.29. 95% CI: 0.33-4.98). In high-grade histologies, UMs were strongly associated with recurrence (HR: 12.1. 95% CI: 1.52-96.6 = 0.019) and disease-specific death (HR: 10.2. 95% CI: 1.12-92.1 = 0.032). The use of UMs in MIS for endometrial cancer was associated with higher rates of recurrence without affecting disease-specific death, except in high-grade histologies.

Introduction and hypothesisThere is a high prevalence of urinary incontinence among endometrial cancer survivors. They are also known to present with pelvic floor muscle alterations. Evidence on the effects of conservative interventions for the management of UI is scarce. This study aims at verifying the effects of an in-home rehabilitation program, including the use of a mobile technology, to reduce UI severity in endometrial cancer survivors.MethodsThis study used a single-case experimental design with replications. Primary outcome for UI severity was the pad test, and secondary outcomes were the ICIQ-UI SF questionnaire and 3-day bladder diary. Pelvic floor muscle function was assessed using 2D-transperineal ultrasound and intravaginal dynamometry. Adherence was documented using mobile technology and an exercise log. Visual and non-parametric analyses of longitudinal data were conducted.ResultsResults show a reduction in UI severity for 87.5% of participants, with a significant relative treatment effect of moderate size (RTE: 0.30). Significant small relative treatment effects were found for the quick contraction and endurance dynamometric tests.ConclusionThis study provides new evidence that endometrial cancer survivors can improve the severity of their UI following an in-home rehabilitation program, including the use of a mobile technology. This mode of delivery has the potential to address a gap in access to pelvic floor physiotherapy services for survivors of EC living in rural and remote communities.

Background: In Part 1 of the phase III RUBY trial (NCT03981796) in patients with primary advanced or recurrent endometrial cancer (EC), dostarlimab plus carboplatin–paclitaxel (CP) significantly improved progression-free survival and overall survival compared with CP alone. Limited safety data have been reported for the combination of immunotherapies plus chemotherapy in this setting. Objectives: The objective of this analysis was to identify the occurrence of treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs) and to describe irAE management in Part 1 of the RUBY trial. Design: RUBY is a phase III, randomized, double-blind, multicenter study of dostarlimab plus CP compared with CP alone in patients with primary advanced or recurrent EC. Methods: Patients were randomized 1:1 to dostarlimab 500 mg, or placebo, plus CP every 3 weeks for 6 cycles, followed by dostarlimab 1000 mg, or placebo, every 6 weeks for up to 3 years. Adverse events (AEs) were assessed according to Common Terminology Criteria for Adverse Events, version 4.03. Results: The safety population included 487 patients who received ⩾1 dose of treatment (241 dostarlimab plus CP; 246 placebo plus CP). Treatment-emergent AEs were experienced by 100% of patients in both arms. TRAEs occurred in 97.9% of the dostarlimab arm and 98.8% of the placebo arm. The most common TRAEs occurred at similar rates between arms and were mostly low grade. IrAEs occurred in 58.5% of patients in the dostarlimab arm and 37.0% of patients in the placebo arm. Dostarlimab- or placebo-related irAEs were reported in 40.7% of patients in the dostarlimab arm and 16.3% of the placebo arm. Conclusion: The safety profile of dostarlimab plus CP was generally consistent with that of the individual components. Dostarlimab plus CP has a favorable benefit–risk profile and is a new standard of care for patients with primary advanced or recurrent EC. Trial registration: NCT03981796. Plain language summary Safety of dostarlimab plus carboplatin-paclitaxel compared with carboplatin-paclitaxel in primary advanced or recurrent endometrial cancer For many years, patients with primary advanced or recurrent endometrial cancer were treated with chemotherapy, specifically with a combination of carboplatin and paclitaxel. Recently, new treatments called immune checkpoint inhibitors have been used to treat endometrial cancer. Dostarlimab, an immune checkpoint inhibitor, is being tested to treat many types of cancer, including endometrial cancer. In the RUBY trial, a combination of dostarlimab plus chemotherapy was compared with chemotherapy alone as treatment for primary advanced or recurrent endometrial cancer. Results showed that patients treated with dostarlimab plus chemotherapy had a lower risk of their cancer becoming worse and a lower risk of dying. Results in this article describe the safety of dostarlimab plus chemotherapy compared with chemotherapy alone. All patients in the RUBY trial experienced at least one adverse event (an undesired effect that happens while receiving treatment or shortly after stopping treatment); most were determined to be caused by the cancer treatments. No differences in the frequency of the overall cancer treatment-related adverse events were seen in patients who received dostarlimab plus chemotherapy compared with those patients who received chemotherapy alone. Some patients experienced an immune-related adverse event. These are a specific type of undesired effect that can occur when patients are treated with immune checkpoint inhibitors. Immune-related adverse events occurred more frequently in patients who received dostarlimab plus chemotherapy than in those who received chemotherapy alone. Physicians were generally able to treat the immune-related adverse events, and only a low percentage of patients discontinued treatment because they experienced an immune-related adverse event. The types of adverse events seen were similar to a combination of those seen in patients who received dostarlimab alone or patients who received chemotherapy alone as treatment for endometrial cancer. Dostarlimab plus chemotherapy is a new standard of care for patients with primary advanced or recurrent endometrial cancer.

Previously, we have identified the RUNX2 gene as hypomethylated and overexpressed in post-chemotherapy (CT) primary cultures derived from serous epithelial ovarian cancer (EOC) patients, when compared to primary cultures derived from matched primary (prior to CT) tumors. However, we found no differences in the RUNX2 methylation in primary EOC tumors and EOC omental metastases, suggesting that DNA methylation-based epigenetic mechanisms have no impact on RUNX2 expression in advanced (metastatic) stage of the disease. Moreover, RUNX2 displayed significantly higher expression not only in metastatic tissue, but also in high-grade primary tumors and even in low malignant potential tumors. Knockdown of the RUNX2 expression in EOC cells led to a sharp decrease of cell proliferation and significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as various genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon RUNX2 suppression, while a number of pro-apoptotic genes and some EOC tumor suppressor genes were induced. Taken together, our data are indicative for a strong oncogenic potential of the RUNX2 gene in serous EOC progression and suggest that RUNX2 might be a novel EOC therapeutic target. Further studies are needed to more completely elucidate the functional implications of RUNX2 and other members of the RUNX gene family in ovarian tumorigenesis.

Summary What is the purpose of this PLS-P? The purpose of this plain language summary of publication is to help you understand recent findings from Part 1 of the RUBY study (full name ENGOT-EN6/GOG3031/RUBY trial). • Researchers sometimes study new combinations of already approved individual treatments to see if the combinations work well together and if they are safe to prescribe to patients. • In Part 1 of the RUBY study, the combination of dostarlimab with carboplatin-paclitaxel was investigated to see how well it worked for patients with primary advanced or recurrent endometrial cancer when compared with patients who were given placebo plus carboplatin-paclitaxel. • Patients in the RUBY study were divided into subgroups according to their biomarker status. This allowed researchers to see if biomarker status could help determine how well patients with specific biomarkers would respond to the combination of dostarlimab with carboplatin-paclitaxel. • This summary reports the results of the second data cut (the second time investigators looked at all of the data since the start of the study) of the RUBY study. At this time, researchers were looking specifically at how long patients lived and how safe the treatment was in patients who received dostarlimab with carboplatin-paclitaxel compared with those patients who received placebo plus carboplatin-paclitaxel.

Background Poly(ADP-ribose) polymerase inhibitors (PARPis) specifically target homologous recombination deficiency (HRD) cells and display good therapeutic effect in women with advanced-stage BRCA1/2-mutated breast and epithelial ovarian cancer (EOC). However, about 50% of high grade serous ovarian cancers (HGSOC) present with HRD due to epigenetic BRCA1 inactivation, as well as genetic/epigenetic inactivation(s) of other HR genes, a feature known as “BRCAness”. Therefore, there is a potential for extending the use of PARPis to these patients if HR status can be identified. Methods We have developed a 3D (spheroid) functional assay to assess the sensitivity of two PARPis (niraparib and olaparib) in ascites-derived primary cell cultures (AsPCs) from HGSOC patients. A method for AsPCs preparation was established based on a matrix (agarose), allowing for easy isolation and successive propagation of monolayer and 3D AsPCs. Based on this method, we performed cytotoxicity assays on 42 AsPCs grown both as monolayers and spheroids. Results The response to PARPis treatment in monolayer AsPCs, was significantly higher, compared to 3D AsPCs, as 88% and 52% of the monolayer AsPCs displayed sensitivity to niraparib and olaparib respectively, while 66% of the 3D AsPCs were sensitive to niraparib and 38% to olaparib, the latter being more consistent with previous estimates of HRD (40%–60%) in EOC. Moreover, niraparib displayed a significantly stronger cytotoxic effect in both in 3D and monolayer AsPCs, which was confirmed by consecutive analyses of the HR pathway activity (γH2AX foci formation) in PARPis-sensitive and resistant AsPCs. Global gene expression comparison of 6 PARPi-resistant and 6 PARPi-sensitive 3D AsPCs was indicative for the predominant downregulation of numerous genes and networks with previously demonstrated roles in EOC chemoresistance, suggesting that the PARPis-sensitive AsPCs could display enhanced sensitivity to other chemotherapeutic drugs, commonly applied in cancer management. Microarray data validation identified 24 potential gene biomarkers associated with PARPis sensitivity. The differential expression of 7 selected biomarkers was consecutively confirmed by immunohistochemistry in matched EOC tumor samples. Conclusion The application of this assay and the potential biomarkers with possible predictive significance to PARPis therapy of EOC patients now need testing in the setting of a clinical trial.

ObjectiveThere is a trend toward less radical surgery in women with small-volume disease who wish to preserve fertility. The objective of our study was to evaluate the oncologic and obstetrical outcome of simple vaginal trachelectomy and lymph node assessment in patients with low-risk early-stage cervical cancer (<2 cm).MethodsFrom May 2007 to January 2020, 50 patients underwent a simple vaginal trachelectomy/conization with laparoscopic sentinel lymph node mapping±complete pelvic node dissection. Patients underwent loop electrocautery excision (LEEP), cone/cervical biopsies, or simple trachelectomy. A preoperative pelvic MRI with gadolinium contrast was systematically performed in all cases. The size of the lesion was established by review of the LEEP, cone or trachelectomy specimen, MRI, and clinical examination. Data was collected prospectively in a computerized database. Descriptive statistics and the Kaplan–Meier estimate were used for analysis.ResultsThe median age was 29 years (range: 21–44) and 35 (70%) patients were nulliparous. As per FIGO 2009 classification, 11 patients had stage IA1 with lymphovascular space invasion (LVSI), 13 patients had stage IA2, and 26 patients had stage IB1. Twenty-six patients had squamous histology, 20 patients adenocarcinoma, and four patients other histologies. On final pathology, lymph nodes were negative in 46 patients (92%), three patients had isolated tumor cells, and one patient had micrometastasis. Thirty patients (60%) had either no residual disease in the trachelectomy specimen (22) or residual dysplasia only (eight). With a median follow-up of 76 months (range: 1–140), only one local recurrence occurred which was treated initially with chemoradiation. She recurred again locally and underwent a pelvic exenteration: the patient progressed again and died of disease. The 5-year progression-free survival and overall survival was 97.9% and 97.6%, respectively. There were 40 pregnancies: five (12.5%) ended in the first trimester, one (2.5%) in the second trimester, and three (7.5%) were late preterm: all the others (30 or 75%) delivered >36 weeks and one pregnancy is ongoing.ConclusionSimple trachelectomy/conization and lymph node assessment is an oncologically safe fertility-preserving surgery in well-selected patients with low-risk early-stage cervical cancer (<2 cm). Obstetrical outcomes are comparable to the general population.

ObjectiveRadical trachelectomy is a valid alternative for the treatment of early-stage cervical cancer in young women who wish to preserve fertility potential. Recent data indicate that even less radical surgery could be performed in low-risk cases. The objective of our study was to evaluate the safety of simple vaginal trachelectomy and node assessment in patients with low-risk, early-stage cervical cancer (<2 cm).MethodsFrom May 2007 to July 2016, 35 women underwent a simple vaginal trachelectomy with laparoscopic sentinel lymph node mapping + pelvic node dissection. Data were collected prospectively in a computerized database. Descriptive statistics and Kaplan-Meier estimate were used for analysis.ResultsPatients’ median age was 29 years, and 24 (69%) were nulliparous. Eight had stage IA1 with lymphovascular space invasion, 9 a stage IA2, and 18 a stage IB1. Nineteen (54%) had squamous histology, 13 (37%) had adenocarcinoma, and 3 had other histologic findings. The median operating room time was 148 minutes (90–240 minutes), and median blood loss was 50 mL (25–200 mL). On final pathology, lymph nodes were negative in all patients, except 2 cases with isolated tumor cells. Twenty-two patients (63%) had either no residual disease in the trachelectomy specimen (n = 15) or residual dysplasia only (n = 7). With a median follow-up of 42 months (1–100 months), 1 local recurrence occurred treated initially with chemoradiation and then a pelvic exenteration. The recurrence-free survival at 48 months is 96.7%. There were 25 pregnancies: 5 (20%) ended in the first trimester, 2 delivered prematurely at 34.4 and at 35 weeks, and all the others (18 [72%]) delivered at more than 36 weeks.ConclusionsBased on our experience, simple trachelectomy and nodes appear to be a safe fertility-preserving surgery in well-selected patients with small-volume cervical cancer. Obstetric outcome appears favorable.

Protein glycosylation perturbations are implicated in a variety of diseases, including cancer. Aberrant glycosylation in cancer is frequently attributed to altered expression of polypeptide GalNAc transferases (GalNAc-Ts) - enzymes initiating mucin-type O-glycosylation. A previous study from our group demonstrated that one member of this family (GALNT3) is overexpressed in epithelial ovarian cancer (EOC), and GALNT3 expression correlated with shorter progression-free survival (PFS) in EOC patients with advanced disease. As considerable degree of redundancy between members of the GalNAc-Ts gene family has been frequently observed, we decided to investigate whether other members of this family are essential in EOC progression. In silico analysis based on publically available data was indicative for altered expression of five GalNAc-Ts (GALNT2, T4, T6, T9 and T14) in ovarian high-grade serous carcinoma (HGSC) samples compared to non-tumoral (control) ovarian tissue. We analyzed protein expression of these GalNAc-Ts in EOC cells and tumors by western blotting, followed by immunohistochemical (IHC) evaluation of their expression in EOC tumor and control samples using tissue microarrays (TMAs). Western blot analyses were indicative for low expression of GALNT2 and strong expression of GALNT6, T9 and T14 in both EOC cells and tumors. These observations were confirmed by IHC. GALNT2 displayed significantly lower expression, while GALNT6, GALNT9 and GALNT14 showed significantly higher expression in HGSC tumors compared to control tissue. Importantly, GALNT6 and GALNT14 expression correlated with poor prognosis of serous EOC patients. Moreover, our results suggest for overlapping functions of some GalNAc-Ts, more specifically GALNT3 and GALNT6, in directing EOC progression. Our results are indicative for a possible implication of different members of the GalNAc-T gene family in modulating EOC progression, and the potential use of GALNT6 and GALNT14 as novel prognostic EOC biomarkers. These data warrant future studies on the role of members of the GalNAc-Ts gene family in ovarian tumorigenesis.