Effect of Adjuvant Chemotherapy in Stage III Cervical Cancer Patients Treated With Concurrent Chemoradiation: A Multicenter Study

Introduction: A significant proportion of cervical cancer (CC) patients are diagnosed at a locally advanced stage. Concurrent chemoradiotherapy (CCRT) is the cornerstone of treatment for patients with locally advanced CC. However, the role of adjuvant chemotherapy (AC) after CCRT is controversial. In this study, we analyzed the efficacy of AC after CCRT in stage III CC patients. Methods: We performed a multicenter, retrospective analysis of 139 FIGO stage III CC patients treated with CCRT of whom 45.3% received AC. Our goal was to determine the impact of AC on survival in these patients. Results: Five-year progression-free survival was 37.5% and 16% in patients receiving CCRT with and without AC, respectively (p=0.008). Median PFS was 30.9 months (CI 95 %14.8-46.9) and 16.6 months (CI 95% 9.3-23.9) in patients receiving CCRT with and without AC, respectively. Five-year overall survival was 78.2% and 28.4% in patients receiving CCRT with and without AC, respectively (p<0.001). Median OS was 132.2 months (CI 95, %66.5-197.8) and 34.9 months (CI 95% 23.1-46.7) in patients receiving CCRT with and in without AC, respectively. Conclusion: Our study suggests that AC provides OS and PFS benefit in stage III CC patients. Larger studies are needed to identify subgroups of patients who would benefit from AC.

Therapeutic Challenges in Patients with Gynecologic Carcinosarcomas: Analysis of a Multicenter National Cohort Study from the French Prospective TMRG Network

Background: Gynecological carcinosarcomas are rare and aggressive diseases, with a poor prognosis. The rarity of these tumors explains the lack of robust and specific data available in the literature. The objective of this study was to investigate the impact of initial adjuvant treatment and recurrent therapeutic strategies. Patients and methods: A multicentric cohort study within the French national prospective Rare Malignant Gynecological Tumors (TMRG) network was conducted. Data from all included carcinosarcomas diagnosed between 2011 and 2018 were retrospectively collected. Results: 425 cases of uterine and ovarian carcinosarcomas (n = 313 and n = 112, respectively) were collected and analyzed from 12 participating centers. At diagnosis, 140 patients (48%) had a FIGO stage III–IV uterine carcinosarcoma (UCS) and 88 patients (83%) had an advanced ovarian carcinosarcoma (OCS) (FIGO stage ≥ III). Two hundred sixty-seven patients (63%) received adjuvant chemotherapy, most preferably carboplatin-paclitaxel regimen (n = 227, 86%). After a median follow-up of 47.4 months, the median progression-free survival (mPFS) was 15.1 months (95% CI 12.3–20.6) and 14.8 months (95% CI 13.1–17.1) for OCS and UCS, respectively. The median overall survival for OCS and UCS was 37.1 months (95% CI 22.2–49.2) and 30.6 months (95% CI 24.1–40.9), respectively. With adjuvant chemotherapy followed by radiotherapy, mPFS was 41.0 months (95% CI 17.0–NR) and 18.9 months (95% CI 14.0–45.6) for UCS stages I–II and stages III–IV, respectively. In the early stage UCS subgroup (i.e., stage IA, n = 86, 30%), mPFS for patients treated with adjuvant chemotherapy (n = 24) was not reached (95% CI 22.2–NR), while mPFS for untreated patients (n = 62) was 19.9 months (95% IC 13.9–72.9) (HR 0.44 (0.20–0.95) p = 0.03). At the first relapse, median PFS for all patients was 4.2 months (95% CI 3.5–5.3). In the first relapse, mPFS was 6.7 months (95% CI 5.1–8.5) and 2.2 months (95% CI 1.9–2.9) with a combination of chemotherapy or monotherapy, respectively (p < 0.001). Conclusions: Interestingly, this vast prospective cohort of gynecological carcinosarcoma patients from the French national Rare Malignant Gynecological Tumors network (i) highlights the positive impact of adjuvant CT on survival in all localized stages (including FIGO IA uterine carcinosarcomas), (ii) confirms the importance of platinum-based combination as an option for relapse setting, and (iii) reports median PFS for various therapeutic strategies in the relapse setting.

Utility of 3T MRI in Women with IB1 Cervical Cancer in Determining the Necessity of Less Invasive Surgery

Purpose: Cervical cancer that is invisible on magnetic resonance imaging (MRI) may suggest lower tumor burden than physical examination. Recently, 3 tesla (3T) MRI has been widely used prior to surgery because of its higher resolution than 1.5T MRI. The aim was to retrospectively evaluate the utility of 3T MRI in women with early cervical cancer in determining the necessity of less invasive surgery. Materials and methods: Between January 2010 and December 2015, a total of 342 women with FIGO stage IB1 cervical cancer underwent 3T MRI prior to radical hysterectomy, vaginectomy, and lymph node dissection. These patients were classified into cancer-invisible (n = 105) and cancer-visible (n = 237) groups based on the 3T MRI findings. These groups were compared regarding pathologic parameters and long-term survival rates. Results: The cancer sizes of the cancer-invisible versus cancer-visible groups were 11.5 ± 12.2 mm versus 30.1 ± 16.2 mm, respectively (p < 0.001). The depths of stromal invasion in these groups were 20.5 ± 23.6% versus 63.5 ± 31.2%, respectively (p < 0.001). Parametrial invasion was 0% (0/105) in the cancer-invisible group and 21.5% (51/237) in the cancer-visible group (odds ratio = 58.3, p < 0.001). Lymph node metastasis and lymphovascular space invasion were 5.9% (6/105) versus 26.6% (63/237) (5.8, p < 0.001) and 11.7% (12/105) versus 40.1% (95/237) (5.1, p < 0.001), respectively. Recurrence-free and overall 5-year survival rates were 99.0% (104/105) versus 76.8% (182/237) (p < 0.001) and 98.1% (103/105) versus 87.8% (208/237) (p = 0.003), respectively. Conclusions: 3T MRI can play a great role in determining the necessity of parametrectomy in women with IB1 cervical cancer. Therefore, invisible cervical cancer on 3T MRI will be a good indicator for less invasive surgery.

The Pretreatment Controlling Nutritional Status Score in Ovarian Cancer: Influence on Prognosis, Surgical Outcome, and Postoperative Complication Rate

Introduction The Controlling Nutritional (CONUT) Status score is an established predictor of impaired prognosis in patients with solid tumors. The aim of this study was to investigate the prognostic value of the CONUT score for overall survival and perioperative complication rates in patients with epithelial ovarian cancer. Patients In this retrospective study we assessed the data of 337 consecutive patients with ovarian cancer. The CONUT score was associated with surgical outcome, postoperative complications and clinicopathological parameters. We used univariate log-rank test and multivariable Cox regression models to evaluate the association between pretreatment CONUT scores and survival. Results A low CONUT score (0 – 2) was associated with an early FIGO stage (p = 0.004), complete tumor resection (p < 0.001), less neoadjuvant chemotherapy (p = 0.017) and other histologies than serous cystadenocarcinoma (p = 0.006). Postoperative complications were observed in 51.4% and 60.5% of patients with a CONUT score of 0 – 2 and a score > 2, respectively (p = 0.161). A shorter overall survival was observed in patients with a CONUT score > 2 compared to patients with a low CONUT score, with 5-year overall survival rates of 31.5% and 58.7%, respectively (p < 0.001). In multivariable analysis, both advanced age (p < 0.001) and FIGO stage (p < 0.001), residual disease (p < 0.001) and a high CONUT score (p = 0.048) were independently associated with unfavorable overall survival. Conclusion Pretreatment CONUT score is an independent prognostic marker for overall survival and associated with successful surgery. Patients with a high CONUT score might benefit from pretreatment nutritional intervention.

EPDR1, Which Is Negatively Regulated by miR-429, Suppresses Epithelial Ovarian Cancer Progression via PI3K/AKT Signaling Pathway

Epithelial ovarian cancer (EOC) is the main pathological type of ovarian cancer. In this study, we found that ependymin-related 1 (EPDR1) was remarkably downregulated in EOC tissues, and low EPDR1 expression was associated with International Federation of Gynecology and Obstetrics (FIGO) stage, metastasis, and poor prognosis. We confirmed that EPDR1 overexpression dramatically suppressed EOC cell proliferation, migration, and invasion in vitro and in vivo. Mechanistically, EPDR1 inhibited EOC tumorigenesis and progression, at least in part, through the repression of the PI3K (Phosphoinositide 3-kinase)/AKT (AKT Serine/Threonine Kinase 1) signaling pathway. Furthermore, the expression and function of EPDR1 were regulated by miR-429, as demonstrated by luciferase reporter assays and rescue experiments. In conclusion, our study validated that EPDR1, negatively regulated by miR-429, played an important role as a tumor-suppressor gene in EOC development via inhibition of the PI3K/AKT pathway. The miR-429/EPDR1 axis might provide novel therapeutic targets for individualized treatment of EOC patients in the future.

Survival Outcomes and Prognostic Predictors in Patients With Malignant Struma Ovarii

Background: Malignant struma ovarii (MSO) is an extremely rare ovarian malignant tumor and there is limited data on the survival outcomes and prognostic predictors of MSO. The objectives of this study were to investigate the disease-free survival (DFS), overall survival (OS), and disease-specific survival (DSS) rates of patients with MSO, and also evaluate the prognostic factors in this population.Methods: A retrospective study was conducted and 194 cases of MSO were selected. DFS was assessed by the logistic regression, OS by the Kaplan–Meier method, and DSS was evaluated by the Cox regression.Results: The median age of these patients was 46.0 years; 142 cases (73.2%) were confined to the ovary and 52 cases (26.8%) had extraovarian metastasis at the initial diagnosis of MSO. During the follow-up, 75.3% of these patients showed no evidence of disease and 18.0% were alive with disease. Only 13 deaths occurred, with 10 attributed to MSO. The 5, 10, and 15-year OS rates were 91.4, 87.7, and 83.5%, respectively. The 5, 10, and 15-year DSS rates were 93.8, 90.0, and 85.7%, respectively. Logistic regression revealed that International Federation of Gynecology and Obstetrics (FIGO) stage IV was the only risk factor for DFS [p &lt; 0.001; odds ratio (OR) 7.328; 95% CI 3.103–16.885, FIGO stage IV vs. stage I; p = 0.021; OR 4.750, 95% CI 1.264–17.856, FIGO stage IV vs. stage II-III]. The multivariate Cox regression analysis showed that poor differentiation was the only risk factor for both OS (p = 0.005, OR 6.406; 95% CI 1.730–23.717) and DSS (p = 0.001, OR 9.664; 95% CI 2.409–38.760), while age ≥45 years was the prognostic predictor for OS (p = 0.038, OR 4.959; 95% CI 1.093–22.508).Conclusion: Survival outcomes were excellent in patients with MSO, irrespective of the treatment strategy, FIGO stage IV, age ≥45 years, and poor differentiation of tumors were the independent risk factors.

MRI-based radiomics analysis to evaluate the clinicopathological characteristics of cervical carcinoma: a multicenter study

Background Preoperative prediction of clinical pathological indicators of cervical cancer (CC) is of great significance to the formulation of personalized treatment plans for CC. Purpose To investigate magnetic resonance imaging (MRI) radiomics analysis for the evaluation of pathological types, tumor grade, FIGO stage, and lymph node metastasis (LNM) of CC. Material and Methods A total of 235 patients with CC from three institutes were enrolled in the study. All patients underwent T2/SPAIR and contrast-enhanced T1-weighted (CE-T1WI) imaging scans before radical hysterectomy by pelvic lymph node dissection surgery. Radiomics features extracted from T2/SPAIR and CE-T1WI imaging were selected by the least absolute shrinkage and selection operator (LASSO) methods for further radiomics signature calculation. These radiomic features were used to construct regression and decision tree models to evaluate the performance of radiomic features in distinguishing clinicopathological indicators. Results The area under the curve (AUC) of T2/SPAIR and CE-T1WI imaging were 0.777 and 0.750, respectively, for differentiating between adenocarcinoma and squamous cell carcinoma. From the two sequences, the AUC of the verification group that distinguished low FIGO stage from high FIGO stage was 0.716 and 0.676, respectively. The AUC for moderately well and poorly differentiated tumors were 0.729 on T2/SPAIR and 0.749 on CE-T1WI imaging. The AUC of the verification groups for LNM was 0.730 and 0.618 on T2/SPAIR and CE-T1WI imaging, respectively. Conclusion MRI radiomics features can be used as a non-invasive method to evaluate the clinicopathological indexes of CC and provide an important auxiliary examination method for patients to determine individualized treatment plans before operation.

Tumor Immune Microenvironment Related Gene-Based Model to Predict Prognosis and Response to Compounds in Ovarian Cancer

BackgroundThe tumor immune microenvironment (TIME) has been recognized to be an imperative factor facilitating the acquisition of many cancer-related hallmarks and is a critical target for targeted biological therapy. This research intended to construct a risk score model premised on TIME-associated genes for prediction of survival and identification of potential drugs for ovarian cancer (OC) patients.Methods and ResultsThe stromal and immune scores were computed utilizing the ESTIMATE algorithm in OC patient samples from The Cancer Genome Atlas (TCGA) database. Weighted gene co-expression network and differentially expressed genes analyses were utilized to detect stromal-and immune-related genes. The Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression was utilized for additional gene selection. The genes that were selected were utilized as the input for a stepwise regression to construct a TIME-related risk score (TIMErisk), which was then validated in Gene Expression Omnibus (GEO) database. For the evaluation of the protein expression levels of TIME regulators, the Human Protein Atlas (HPA) dataset was utilized, and for their biological functions, the TIMER and CIBERSORT algorithm, immunoreactivity, and Immune Cell Abundance Identifier (ImmuCellAI) were used. Possible OC medications were forecasted utilizing the Genomics of Drug Sensitivity in Cancer (GDSC) database and connectivity map (CMap). TIMErisk was developed based on ALPK2, CPA3, PTGER3, CTHRC1, PLA2G2D, CXCL11, and ZNF683. High TIMErisk was recognized as a poor factor for survival in the GEO and TCGA databases; subgroup analysis with FIGO stage, grade, lymphatic and venous invasion, debulking, and tumor site also indicated similar results. Functional immune cells corresponded to more incisive immune reactions, including secretion of chemokines and interleukins, natural killer cell cytotoxicity, TNF signaling pathway, and infiltration of activated NK cells, eosinophils, and neutrophils in patients with low TIMErisk. Several small molecular medications which may enhance the prognosis of patients in the TIMErisk subgroup were identified. Lastly, an enhanced predictive performance nomogram was constructed by compounding TIMErisk with the FIGO stage and debulking.ConclusionThese findings may offer a valuable indicator for clinical stratification management and personalized therapeutic options for OC patients and may be a foundation for future mechanistic research of their association.

An Immune-Related Long Noncoding RNA Signature as a Prognostic Biomarker for Human Endometrial Cancer

Background. Endometrial cancer is among the most common malignant tumors threatening the health of women. Recently, immunity and long noncoding RNA (lncRNA) have been widely examined in oncology and shown to play important roles in oncology. Here, we searched for immune-related lncRNAs as prognostic biomarkers to predict the outcome of patients with endometrial cancer. Methods. RNA sequencing data for 575 endometrial cancer samples and immune-related genes were downloaded from The Cancer Genome Atlas (TCGA) database and gene set enrichment analysis (GSEA) gene sets, respectively. Immune-related lncRNAs showing a coexpression relationship with immune-related genes were obtained, and Cox regression analysis was performed to construct the prognostic model. Survival, independent prognostic, and clinical correlation analyses were performed to evaluate the prognostic model. Immune infiltration of endometrial cancer samples was also evaluated. Functional annotation of 12 immune-related lncRNAs was performed using GSEA software. Prognostic nomogram and survival analysis for independent prognostic risk factors were performed to evaluate the prognostic model and calculate the survival time based on the prognostic model. Results. Twelve immune-related lncRNAs (ELN-AS1, AC103563.7, PCAT19, AF131215.5, LINC01871, AC084117.1, NRAV, SCARNA9, AL049539.1, POC1B-AS1, AC108134.4, and AC019080.5) were obtained, and a prognostic model was constructed. The survival rate in the high-risk group was significantly lower than that in the low-risk group. Patient age, pathological grade, the International Federation of Gynecology and Obstetrics (FIGO) stage, and risk status were the risk factors. The 12 immune-related lncRNAs correlated with patient age, pathological grade, and FIGO stage. Principal component analysis and functional annotation showed that the high-risk and low-risk groups separated better, and the immune status of the high-risk and low-risk groups differed. Nomogram and receiver operating characteristic (ROC) curves effectively predicted the prognosis of endometrial cancer. Additionally, age, pathological grade, FIGO stage, and risk status were all related to patient survival. Conclusion. We identified 12 immune-related lncRNAs affecting the prognosis of endometrial cancer, which may be useful as therapeutic targets and molecular biomarkers.

Biomarkers of Central Nervous System Involvement from Epithelial Ovarian Cancer

Epithelial ovarian cancer (EOC) is the leading cause of death among women affected by gynaecological malignancies. Most patients show advanced disease at diagnosis (FIGO stage III-IV) and, despite the introduction of new therapeutic options, most women experience relapses. In most cases, recurrence is abdominal-pelvic; however, EOC can occasionally metastasize to distant organs, including the central nervous system. The incidence of brain metastases (BMs) from EOC is low, but it has grown over time; currently, there are no follow-up strategies available. In the last decade, a few biomarkers able to predict the risk of developing BMs from OC or as potential therapeutic targets have been investigated by several authors; to date, none have entered clinical practice. The purpose of this review is to offer a summary on the role of the most relevant predictors of central nervous system (CNS) involvement (hormone receptors; BRCA; MRD1; PD-1/PD-L1) and to highlight possible therapeutic strategies for the management of metastatic brain disease in EOC