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The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, is expressed in up to 70% of epithelial ovarian cancers (EOCs), where it correlates with poor prognosis. The majority of EOCs are diagnosed at an advanced stage, and at least 50% present malignant ascites. High levels of IL-6 have been found in the ascites of EOC patients and correlate with shorter survival. Herein, we investigated the signaling cascade led by EGFR activation in EOC and assessed whether EGFR activation could induce an EOC microenvironment characterized by pro-inflammatory molecules. In vitro analysis of EOC cell lines revealed that ligand-stimulated EGFR activated NFkB-dependent transcription and induced secretion of IL-6 and plasminogen activator inhibitor (PAI-1). IL-6/PAI-1 expression and secretion were strongly inhibited by the tyrosine kinase inhibitor AG1478 and EGFR silencing. A significant reduction of EGF-stimulated IL-6/PAI-1 secretion was also obtained with the NFkB inhibitor dehydroxymethylepoxyquinomicin. Of 23 primary EOC tumors from advanced-stage patients with malignant ascites at surgery, 12 co-expressed membrane EGFR, IL-6 and PAI-1 by immunohistochemistry; both IL-6 and PAI-1 were present in 83% of the corresponding ascites. Analysis of a publicly available gene-expression data set from 204 EOCs confirmed a significant correlation between IL-6 and PAI-1 expression, and patients with the highest IL-6 and PAI-1 co-expression showed a significantly shorter progression-free survival time ( P =0.028). This suggests that EGFR/NFkB/IL-6-PAI-1 may have a significant impact on the therapy of a particular subset of EOC, and that IL-6/PAI-1 co-expression may be a novel prognostic marker.

ObjectivesPerivascular epitheliod cell tumors (PEComas) are rare mesenchymal neoplasms. Uterine PEComa is extremely rare and only limited evidence is still available.MethodsCharts of consecutive patients who had treatment (between 01/01/2010 and 12/31/2020) for newly diagnosed uterine PEComas were retrieved. Five-year outcomes were assessed using Kaplan-Meier and Cox hazard models.ResultsData of 23 patients with newly diagnosed PEComas were analyzed. Mean (SD) patients‘ age was 52 (14) years. Twenty-two patients had a surgical cytoreductive attempt. In one case surgery was not performed due to the presence of an extra-abdominal spread. Overall, seven (30%) patients had disease outside the uterus at the time of surgery. Complete cytoreduction (no macroscopic residual tumor) was achieved in 19 patients. Eleven (48%) patients had adjuvant treatments, consisting in anthracycline-based chemotherapy (n=4),gemcitabine-based chemotherapy (n=2), mTOR inhibitors (n=4) and hormonal treatment (n=1). Median (range) follow-up as 23 (2, 99) months. Eleven (48%) recurrences occurred with a mean (SD) progression free-survival of 14 (11) months. After a median (range) follow-up of 23 (2–99) months, nine (39%) patients died of disease. Residual tumor at surgery was the only factor correlating with the risk of developing recurrent disease (p=0.023) and worse overall survival (p=0.014). In our small series, stage of disease and adjuvant therapy administration had no impact on survival outcomes.ConclusionsUterine PEComa represents a rare and aggressive entity. Molecular/genomic profiling of the disease is necessary to predict response to treatment. Further collaborative investigations are warranted to assess the role of various prognostic factors and evaluate the most effective surgical and medical treatment modalities

ObjectivesTo report on the performance of hysteroscopic injection of indocyanine green (ICG) for sentinel lymph node mapping (SNM) in endometrial cancerMethodsThis is a retrospective cohort study of consecutive endometrial cancer patients who had SNM via hysteroscopic injection of IGC between 2013 and 2017. Detection rate, accuracy, and oncologic outcomes were evaluatedResultsCharts of 52 patients were evaluated. At least one sentinel node was detected in 95% of patients. Bilateral pelvic mapping was found in 74% of cases. In 45% of cases, SLNs mapped in both pelvic and para-aortic nodes, and four cases (8%) in the para-aortic area, only. In three patients (6%) sentinel nodes were found in aberrant (parametrial/presacral) areas. Seven (13.5%) patients were diagnosed with nodal involvement. Low volume disease was observed in four (8%) patients (2 with isolated tumor cells and 2 with micrometastasis). After a median (range) follow-up of 34.7 (10, 61) months, five (9.6%) patients developed recurrences: two abdominal/distant, one vaginal, and one nodal (in the para-aortic area in a patient diagnosed with endometrioid G1 endometrial cancer and isolated tumor cells in a pelvic node). No patient died of disease.ConclusionsHysteroscopic injection of ICG ensures delineation of lymphatic drainage from the tumor area, thus achieving accurate detection of sentinel nodes. Further evidence is warranted to assess the role of hysteroscopic injection in identifying extrapelvic sentinel nodes.

Introduction/Background*Perivascular epitheliod cell tumors (PEComas) are rare mesenchymal neoplasms. Uterine PEComa is extremely rare and only limited evidence is still available.MethodologyThis is a single-center retrospective study. Charts of consecutive patients who had treatment (from 01/01/2010 to 12/31/2020) for newly diagnosed uterine PEComas were retrieved. Five-year survival outcomes were assessed using Kaplan-Meier and Cox proportional hazard models.Result(s)*Data of 23 patients with newly diagnosed PEComas were analyzed. Mean (SD) patients‘ age was 52 (14) years. Twenty-two patients had a surgical cytoreductive attempt. In one case surgery was not performed due to the presence of an extra-abdominal spread. Overall, seven (30%) patients had disease outside the uterus at the time of surgery. Complete cytoreduction (no macroscopic residual tumor) was achieved in 19 patients. Complete cytoreduction was not completed in three patients who gross extrauterine disease and in the aforementioned patient who had not surgery. Eleven (48%) patients had adjuvant treatments, consisting in anthracycline-based chemotherapy (n=4),gemcitabine-based chemotherapy (n=2), mTOR inhibitors (n=4) and hormonal treatment (n=1). Median (range) follow-up as 23 (2, 99) months. Eleven (48%) recurrences occurred with a mean (SD) progression free-survival of 14 (11) months. After a median (range) follow-up of 23 (2, 99) months, nine (39%) patients died of disease. Residual tumor at surgery was the only factor correlating with the risk of developing recurrent disease (p=0.023) and worse overall survival (p=0.014). In our small series, stage of disease and adjuvant therapy administration had no impact on survival outcomes.Conclusion*Uterine PEComa represents a rare and aggressive entity. Molecular/genomic profiling of the disease is necessary to predict response to treatment. Further collaborative investigations are warranted to assess the role of various prognostic factors and evaluate the most effective surgical and medical treatment modalities.

Introduction/BackgroundAccumulating data highlighted that minimally invasive surgery has been associated with higher recurrence rates and worse overall survival than the open approach in women with early-stage cervical cancer. Tumor spread at the time of colpotomy might be advocate as the reason of tumor cells dissemination in the pelvic area. Here, we aimed to investigate if primary conization might overcome the risk of local dissemination in early-stage cervical cancer undergoing laparoscopic radical hysterectomy.MethodologyConsecutive data of 262 early stage cervical cancer patients were retrieved: 88 women had conization followed by radical hysterectomy. A propensity-matched comparison (1:1) was carried out in order to compare laparoscopy and open surgery, minimizing possible selection biases.ResultsData of 35 patients’ pair (total 70 patients) were analyzed. No between-group differences in baseline, disease and pathological variables were observed (p>0.20). Patients undergoing laparoscopy experienced a slightly non-significant longer operative time than patients undergoing open surgery (210.8 (±47.7) vs. 187.9 (±24.7) minutes; p=0.089); while laparoscopic approach correlated whit lower blood loss (50 (range, 30–100) vs. 150 (range, 50–500) ml; p<0.001) and shorter length of stay (3 (±0.8) vs. 5.4 (±1.4) days; p<0.001) in comparison to open surgery. Morbidity rate was similar between groups (p=1.00). One local recurrence was observed per group (p=1.00). Type of surgical approach did not influence site of recurrence (p=1.00) as well as survival outcomes, in term of 10-year disease-free (p=0.549, log-rank test) and overall survivals (p=0.615, log-rank test).ConclusionOur data seems underline that primary conization might overcome the risk of local recurrence following laparoscopic radical hysterectomy in early-stage cervical cancer. Further prospective evidence is needed.DisclosureNothing to disclose.

Introduction/BackgroundLynch syndrome (LS) is a well know risk factor for developing endometrial carcinoma (EC). Here, we aimed to investigate the impact of gene-specific germline pathogenic variants on clinical features of EC.MethodologyThis is a retrospective case series of consecutive surgically-treated patients with histological diagnosis of EC and with a germline pathogenic variant in mismatch repair genes. Classes of risk are graded per the ESGO-ESGO-ESTRO guidelines.ResultsOverall, 68 patients with EC and LS were evaluated. Ten (14.7%) patients were excluded due to absence of clear information about the gene involved in LS, thus leaving 58 (85.3%) patients available for the final analysis. MLH1, MSH2 and MSH6 pathogenic variants were observed in 19 (32.7%), 33 (56.9%) and 6 (10.3%) cases, respectively. Mean (SD) age at EC diagnosis was 51 (±6.4), 43.5 (±7.4) and 60.3 (±8.8) years (p=0.0002). Prevalence of non-endometrioid EC were 15.7%, 24.2% and 0% in MLH1, MSH2 and MSH6 group, respectively (p=0.345). Focusing on classes of risk we observed that patients harboring a MLH1 or MSH2 pathogenic variant were at higher risk than patients with a MSH6 mutation. In fact, according to the ESMO-ESGO-ESTRO classification, low, intermediate, and high risk EC accounted in 47.3%, 10.5% and 42.1% of MLH1 group, in 57.6%, 3% and 39.4% of MSH2 group and in 50%, 50% and 0% of MSH6 group (p=0.009).ConclusionPatients with MLH1 and MSH2 pathogenic variants are at a higher risk of early onset of EC and are characterized by more aggressive disease than patients with MSH6 pathogenic variants.DisclosureNothing to disclose.

Introduction/BackgroundTo investigate the impact of laparoscopic surgery on short- and medium-term outcomes of cervical cancer patients undergoing nerve-sparing radical hysterectomy.MethodologyData of consecutive patients affected by locally-advaced cervcial cancer who had neoadjuvant chemotherapy followed by laparoscopic nerve-sparing radical hysterectomy were matched 1:1 with an historical cohort of patients undergoing neoadjuvant chemotherapy followed by open radical hysterectomy, using propensity matching algorithm.ResultsThirty-five patients’ pairs (70 patients: 35 undergoing laparoscopic vs. 35 undergoing open abdominal nerve-sparing radical hysterectomy) were included. Demographic and baseline oncologic characteristics were balanced between groups. Patients undergoing laparoscopic surgery had similar operative time than patients undergoing open abdominal procedures (249 [±91.5] vs. 223 [±65.0] minutes; p=0.066). Laparoscopic approach correlated with lower blood loss (30.5 [±11.0] vs. 190 [90.4] mL; p<0.001) and shorter hospital stay (3.2 [±1.2] vs. 5.4 [2.0] days; p=0.023). Patients undergoing laparoscopy experienced a lower 30-day pelvic floor dysfunction rate than patients having open surgery (p=0.024). Moreover, they experienced shorter recovery of bladder function than patients having open procedures (median, 7 vs. 9 days; p=0.004, log-rank test). After a median follow-up of 51.7 and 14.7 months for open abdominal and minimally invasive procedures, disease-free (p=0.617) and overall (p=0.814) survivals were similar between groups. Using multivariate model, we observed that the adoption of laparoscopic approach did not impact on disease-free (HR: 1.32 (95%CI: 0.58, 3.01); p=0.50) and overall (HR: 1.26 (95%CI: 0.41, 3.81); p=0.67) survivals.ConclusionLaparoscopic nerve sparing radical hysterectomy resulted in improved short-term outcomes, without impacting on medium-term oncologic outcomes. Further prospective trials are needed to assess long-term outcomes of patients having minimally invasive surgery.DisclosureNothing to disclose.

ObjectivesSentinel node mapping is increasingly being utilized for endometrial cancer staging. However, only limited evidence supporting the adoption of sentinel node mapping instead of conventional lymphadenectomy is still available. Here, we aimed to review the current evidence comparing sentinel node mapping and lymphadenectomy in endometrial cancer staging.MethodsThis systematic review was registered in the International Prospective Register of Systematic Reviews. Der-Simonian and Laird random-effects models were used to pool log transformed event rates and estimated 95%CI for dichotomous outcomes between the two interventions for each study and we pooled the effect size using the same models.ResultsOverall, 3,536 patients were included: 1,249 (35.3%) and 2,287 (64.7%), undergoing sentinel node mapping and lymphadenectomy, respectively. Pooled data suggested that positive pelvic nodes were detected in 184 out of 1,249 (14.7%) patients having sentinel node mapping and 228 out of 2,287 (9.9%) patients having lymphadenectomy (OR:2.03; (95%CI:1.30 to 3.18);p=0.002). No difference in detection of positive nodes located in the paraaortic was observed (OR:0.93 (95%CI:0.39 to 2.18); p=0.86). Overall recurrence rate was 4.3% and 7.3% after sentinel node mapping and lymphadenectomy, respectively (OR:0.90 (95%CI:0.58 to 1.38); p=0.63). Similarly, nodal recurrences were statistically similar between groups (1.2% vs. 1.7%; OR: 1.51 (95%CI:0.70 to 3.29); p=0.29).ConclusionsIn conclusion, our meta-analysis underlines that sentinel node mapping is non-inferior to standard lymphadenectomy in term of detection of paraaortic nodal involvement and recurrence rates (any site and nodal recurrence); while, focusing on the ability to detect positive pelvic nodes, sentinel node mapping could be consider superior to lymphadenectomy.

Introduction/Background*The role of volume of sentinel lymph nodes (SLNs) disease (macro-micrometastases and ITCs) in endometrial cancer is not clearly defined. We aimed to asses predictive factors for SLNs involvement and recurrence free survival (RFS) in patients with endometrial cancer.MethodologyA multicenter retrospective evaluation of endometrial cancer patients with positive (macro-micro metastases or ITCs) SLNs, treated between 2003 and 2020, was performed. Predictive factors for nodal involvement (endometrioid vs non-endometrioid histology, grading, lymphovascular-space invasion (LVSI), myometrial invasion (MI), cervical stromal invasion, ESGO/ESTRO/ESP risk group), adjuvant therapy and oncological outcomes were evaluated.Result(s)*142 patients were identified among 12 participating centers performing SLN mapping. In 64.8% of cases a low-volume disease (≤2 mm) was found in SLNs: 33 (23.2%) ITCs and 59 (41.6%) micrometastases. Factors influencing volume of nodal metastases were: grading [p:0.002] (G1 associated with low-volume disease), LVSI [p:0.007] and MI >50% [p:0.008] (both associated with macrometastases). There were: 20 (14.1%) low-risk, 14 (9.8%) intermediate, 88 (62%) high-intermediate and 20 (14.1%) high-risk according to 2020-ESGO/ESTRO/ESP risk group (on uterus). 17 (18.5%) patients with low-volume disease (8 micrometastases and 9 ITCs) did not receive any adjuvant therapy. At a mean follow-up of 34.6 months (range 1 –215) months, 21 (14.8%) relapses were recorded, only one among patients not receiving any adjuvant, none in the ESGO/ESTRO/ESP low risk group. The RFS at 2-years for the micrometastatic patients was 91%, similar to ITCs patients (79.1%), regardless of adjuvant treatment, but statistically better than patients with macrometastases (72.3%) [p: 0.026]. There was a trend to distinct RFS according to ESGO/ESTRO/ESP risk group, but none of the comparisons reached significance. The only factors affecting RFS were deep MI [p:0.03] and cervical stromal invasion [p:0.046].Conclusion*More than half of patients with positive SLNs had low-volume disease. Grading, MI and LVSI predicted volume of nodal metastases. MI and cervical invasion affected RFS; while adjuvant treatment did not seem significantly associated with RFS in patients with low-volume disease. Longer follow-up time and a larger sample size are needed to understand the role of adjuvant therapy in low-volume metastatic SLNs.

Introduction/Background*Uterine serous carcinoma (USC) accounts for 10% of all endometrial cancer; however, it carries the poorest prognosis, with 5-year survival rates as low as 55%. According to NCCN guidelines first-line treatment is comprehensive surgical staging by laparotomy/laparoscopy, and maximal cytoreduction to no residual disease in advanced stages. However, due to the rarity and unfavorable prognosis of the disease, available evidence is scanty and controversial on risk factors staging, adjuvant treatment, and outcome of USC.Therefore, a retrospective study on women with USC undergoing surgery was performed to better elucidate oncologic outcomes of these patients.MethodologyThis is a retrospective analysis of a prospectively collected database of consecutive patients with USC who underwent surgery between 2000-2020 at a tertiary referral center for gynecologic oncology. The primary objective of this study were progression-free (PFS) and overall survival (OS) outcomes, evaluated using Kaplan-Meier and Cox proportional hazard models.Result(s)*147 consecutive patients were finally included in the study. Median (IQ range) age and BMI were 66 (39-71) years and 25 (39-71) kg/m2, respectively. Stage distribution was as follows: 67 (45.6%) with early stage (stage I/II) with uterine confined disease and 80 (54.4%) with advanced stages (stage III/IV) disease. The median follow-up period was 78.6 months (IQ range = 35.7-117.3 months). The overall recurrence rate was 41% (60 patients), early-stage disease recurrence was 28.4% (19 out of 67) while advanced stage disease recurrence was 51.3% (41 out of 80). The 5-year PFS rate was 35.0% (95% confidence interval [CI]: 27.5-44.7%). At multivariate analysis, age, BMI, depth of myometrial invasion, cytology, and optimal cytoreduction with postoperative residual tumor absence significantly influenced PFS. The 5-year OS rates were 46.5% (95% CI: 38.1-56.8]. Multivariate analysis showed that optimal cytoreduction and accuracy of retroperitoneal surgery were the only two variables influencing OS.Conclusion*Among patients with apparent early-stage USC, peritoneal and retroperitoneal staging allows to identify those with disease harboring outside the uterus. Comprehensive surgical staging and optimal cytoreduction are the most significant prognostic factors affecting survival. Further collaborative studies are warranted in order to improve outcomes of serous endometrial cancer patients.