Clinical and Translational Oncology

Zinc fingers and homeoboxes 2 inhibition could suppress the proliferation of ovarian cancer cells by apoptosis pathway

The Zinc fingers and homeoboxes (ZHX) protein family has been reported to be involved in tumor development; however, it remains controversial whether these proteins can act as promoters or inhibitors of cancer development. The current study focused on the biological role of ZHX2 in ovarian cancer. Tissue microarrays were established using 154 ovarian cancer samples. Immunohistochemical analysis was employed to determine the expression levels of ZHX2 in ovarian cancer samples. The prognostic analysis was performed using the Kaplan-Meier method and compared with a log-rank test. The specific role of ZHX2 in ovarian cancer was investigated in cell lines in vitro. It was found that ZHX2 was not significantly overexpressed in ovarian cancer samples; however, its expression was significantly correlated with advanced tumor grade. Patient survival analysis indicated that patients with high expression of ZHX2 exhibited worse overall survival rate compared with those with low expression of ZHX2. Furthermore, univariate and multivariate analyses demonstrated that ZHX2 was an independent prognostic factor of progression-free survival in patients with ovarian cancer. In vitro experiments indicated that inhibition of ZHX2 could significantly suppress ovarian cancer cell proliferation via induction of the apoptotic pathway. The data indicated that ZHX2 may be considered a promising biomarker in ovarian cancer and that inhibition of its expression may be a potential therapeutic target in ovarian cancer treatment.

Correlation of PD-L1 expression with different clinico-pathological and immunohistochemical features of ovarian surface epithelial tumors

Abstract Background Primary carcinoma of the ovary (OCs) are responsible for a significant number of deaths related to cancer, and have the highest rate of death related to cancers of the female reproductive organs. Programmed cell death 1 (PD1) protein, acts as an immune checkpoint, and has an important role in the down-regulation of the immune system by preventing the activation of T-cells, which will weaken the autoimmunity and increases self-tolerance. This study aimed at the evaluation of the immunohistochemical (IHC) expression of PD-L1 in various primary surface ovarian epithelial tumours and to test its correlation with different clinicopathological parameters together with the expression of a panel of P53, ER and PR. Methods A set of 102 cases of primary ovarian surface epithelial neoplasms (benign, borderline and malignant) were collected to construct Tissue Microarray (TMA) using 3 tissue cores from each case. IHC for PD-L1, p53, PR and ER was performed. The expression of PD-L1 was evaluated in relation to some clinicopathological parameters and to the expression patterns of other markers. Results Expression of PD-L1 was detected in about 51% (n = 36) of malignant tumours. The malignant group significantly showed PD-L1 positivity compared to borderline and benign groups. The malignant tumours significantly showed PD-L1 and total p53 positivity in comparison to borderline group. Also, malignant tumours significantly showed higher combined positivity of PD-L1 and either PR or ER compared to borderline and benign lesions. No significant correlation was appreciated between PD-L1 expression and with any of the studied clinicopathological parameters. Conclusions This study showed a significant PD-L1 expression in malignant primary surface epithelial tumours. Construction of a panel of IHC markers, including PD-L1, could have a potential value to define patients those would benefit from the addition of immunotherapy to the treatment plan.

SEOM–GEICO clinical guideline on epithelial ovarian cancer (2023)

AbstractIn recent years, the incorporation of new strategies to the therapeutic armamentarium has completely changed the outcomes of epithelial ovarian cancer (EOC). The identification of new predictive and prognostic biomarkers has also enabled the selection of those patients more likely to respond to targeted agents. Nevertheless, EOC is still a highly lethal disease and resistance to many of these new agents is common. The objective of this guideline is to summarize the most relevant strategies to manage EOC, to help the clinician throughout the challenging diagnostic and therapeutic processes and to provide evidence-based recommendations.

UBE2T is a diagnostic and prognostic biomarker for endometrial cancer

Abstract Background Endometrial cancer (UCEC) is one of the most common malignant tumors in gynecology, and early diagnosis is crucial for its treatment. Currently, there is a lack of early screening tests specific to UCEC, and treatment advances are limited. It is crucial to identify more sensitive biomarkers for screening, diagnosis, and predicting UCEC. Previous studies have shown that UBE2T is involved in the development of various tumors such as breast cancer and liver cancer, but research on the role of UBE2T in UCEC is limited. Methods Using data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and UALCAN databases, we analyzed the differential expression of UBE2T mRNA and protein in endometrial cancer (UCEC), along with its clinical relevance. A total of 113 clinical samples were collected, and immunohistochemistry and Western blot analysis were employed to validate bioinformatics analysis results. Volcano plots were generated using UBE2T and its differentially expressed genes, and a protein–protein interaction (PPI) network was constructed. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), and immune infiltration analysis were used to predict the functional role of UBE2T in UCEC progression. Correlation between UBE2T expression and patient survival was analyzed using TCGA data, and Kaplan–Meier survival curves were plotted. Results UBE2T is significantly overexpressed in UCEC and correlates with poor prognosis. Its overexpression is closely associated with mitosis, cell cycle regulation, and histological grade in UCEC patients. Conclusion UBE2T is highly expressed in UCEC and suppresses anti-tumor immune responses in UCEC patients. It serves as a key participant in UCEC progression, associated with a range of adverse outcomes, and holds potential as a clinical diagnostic and prognostic biomarker.

Engrailed-2 (EN2) protein in cervical mucus: a novel biomarker for endometrial carcinoma

Abstract Objective This study aims to demonstrate that the EN2 protein in cervical mucus may serve as a novel biomarker for screening endometrial cancer. Materials and Methods This study included 133 patients who were treated at Beijing Obstetrics and Gynecology Hospital. According to the pathological results of hysteroscopy endometrial biopsy, the patients were divided into endometrial cancer group (n = 55), endometrial atypical hyperplasia group (n = 16), benign lesion group (n = 28), and control group (n = 34). All patients collected cervical mucus before hysteroscopy, and the level of EN2 protein in cervical mucus was detected by ELISA in the four groups of patients. Nine patients who underwent surgical treatment for endometrial cancer were included, and endometrial cancer lesions and adjacent tissues without endometrial cancer infiltration were taken from the endometrial cancer lesions and cervical tissues. Fifteen patients who underwent hysterectomy for benign lesions were included, and endometrial and cervical tissues were taken from the endometrial cancer lesions and adjacent tissues without endometrial cancer infiltration. PT-PCR, immunohistochemistry, and WB were used to verify the expression differences of EN2 protein in cancerous lesions and endometrial tissues without endometrial infiltration, cervical tissues, and endometrial tissues without endometrial lesions. In addition, HEC1B, KLE, and HeLa cell lines were used to characterize EN2 overexpression in endometrial cancer cells. Immunohistochemistry, RT-PCR, and confocal analysis were used to detect the expression of EN2 protein in different cell lines. Results In different groups, the average concentration of EN2 protein in cervical mucus in the EC group was significantly higher than that in the benign group and the normal control group (573.9 ± 123.4 ng/mL vs 153.5 ± 106.2 ng/mL and 153.0 ± 107.5 ng/mL, P < 0.001). The concentration of EN2 protein in EIN3 case specimens was significantly higher than that in the normal control group (P < 0.001). ROC analysis showed that the optimal threshold for diagnosing endometrial cancer in cervical mucus was 321.1 ng/ml, with a sensitivity of 92.6% and specificity of 95.4% for distinguishing EINIII, EC, and non-cancerous cases. In clinical specimens, the expression level of EN2 protein in endometrial cancer tissues was significantly higher than that in endometrial tissues and cervical tissues without endometrial cancer infiltration. In addition, PT-PCR, immunohistochemistry, suggest that EN2 protein is overexpressed in endometrial cancer cell lines compared to cervical adenocarcinoma cells (P < 0.01). Conclusion The concentration of EN2 protein in cervical mucus can effectively identify endometrial cancer and precancerous lesions. The increased expression of EN2 protein in endometrial cancer lesions leads to an increase in the concentration of EN2 protein in the cervical mucus of endometrial cancer patients.This is a small single-center study, and larger studies are needed to determine the role of EN2 protein in the diagnosis of endometrial cancer.

The cuproptosis-related gene UBE2D2 functions as an immunotherapeutic and prognostic biomarker in pan-cancer

Cuproptosis, as a unique modality of regulated cell death, requires the involvement of ubiquitin-binding enzyme UBE2D2. However, the prognostic and immunotherapeutic values of UBE2D2 in pan-cancer remain largely unknown. Using UCSC Xena, TIMER, Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Human Protein Atlas (HPA) databases, we aimed to explore the differential expression pattern of UBE2D2 across multiple cancer types and to evaluate its association with patient prognosis, clinical features, and genetic variations. The association between UBE2D2 and immunotherapy response was assessed by gene set enrichment analysis, tumor microenvironment, immune gene co-expression and drug half maximal inhibitory concentration (IC50) analysis. The mRNA and protein levels of UBE2D2 were markedly elevated in most cancer types, and UBE2D2 exhibited prognostic significance in liver hepatocellular carcinoma (LIHC), kidney chromophobe (KICH), uveal melanomas (UVM), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), and kidney renal papillary cell carcinoma (KIRP). UBE2D2 expression was correlated with clinical features, tumor mutation burden, microsatellite instability, and anti-tumor drug resistance in several tumor types. Gene enrichment analysis showed that UBE2D2 was significantly associated with immune-related pathways. The expression level of UBE2D2 was correlated with immune cell infiltration, including CD4 + T cells、Macrophages M2、CD8 + T cells in pan-cancer. PDCD1, CD274 and CTLA4 expression levels were positively correlated with UBE2D2 level in multiple cancers. We comprehensively investigated the potential value of UBE2D2 as a prognostic and immunotherapeutic predictor for pan-cancer, providing a novel insight for cancer immunotherapy.

miRNA-576-5p promotes endometrial cancer cell growth and metastasis by targeting ZBTB4

Abstract Purpose MicroRNAs (miRNAs) have already been shown to have a strong correlation with the invasion and metastasis capacity of tumor cells. The present research examined the function of miRNA-576-5p (miR-576-5p) in the development of endometrial cancer (EC). Methods miR-576-5p and ZBTB4 expression in EC and benign endometrial tissues was measured using quantitative real-time PCR (qRT-PCR) and western blot. To evaluate the proliferation ability of tumor cells in vitro, 2,5-diphenyl-2H-tetrazolium bromide (MTT) and colony formation assays were carried out. The effect of miR-576-5p on the proliferation ability of EC cells in vivo was measured by the tumor formation in nude mice. The migration and invasion ability of tumor cells was determined using the transwell assay. To confirm the association between expressions of miR-576-5p and zinc finger and BTB domain containing four (ZBTB4), western blot, qRT-PCR, and luciferase assay were carried out. Results miR-576-5p expression increased significantly in EC samples than in benign endometrial tissues. The level of miR-576-5p was significantly higher in the polymerase ε (POLE) ultramutated subgroup compared to the other three subgroups. High levels of miR-576-5p expression were linked to a shorter progression-free interval time in the copy number high subgroup. Furthermore, upregulated miR-576-5p facilitated EC cell invasion and migration in vitro and promoted the proliferation of EC tumor cell lines both in vitro and in vivo. Moreover, this study showed that the expression of ZBTB4 decreased in patients with EC, and the dual-luciferase reporter assay confirmed that miR-576-5p binds directly to the 3′-UTR of ZBTB4 and inhibits the expression of ZBTB4. An increase in miR-576-5p expression leads to a decrease in the mRNA and protein expression level of ZBTB4. The effects of miR-576-5p can be reversed by overexpression of ZBTB4. Conclusion miR-576-5p promoted proliferation and metastasis capacity of EC cells by inhibiting ZBTB4 expression. We hypothesized that miR-576-5p could be a prospective therapeutic target for EC.

Risk of endometrial cancer after RRSO in BRCA 1/2 carriers: a multicentre cohort study

Abstract Objective To know the risk of endometrial cancer (EC) in a population of women with BRCA 1/2 pathogenic or likely pathogenic variants after risk-reducing salpingo-oophorectomy (RRSO). Methods The study cohort included data from 857 women with BRCA mutations who underwent RRSO visited four hospitals in Catalonia, Spain, from January 1, 1999 to April 30, 2019. Standardized incidence ratio (SIR) of EC was calculated in these patients using data from a regional population-based cancer registry. Results After RRSO, eight cases of EC were identified. Four in BRCA 1 carriers and four in BRCA2 carriers. The expected number of cases of EC was 3.67 cases, with a SIR of 2.18 and a 95% CI (0.93–3.95). Conclusions In our cohort, the risk of EC in BRCA1/2 carriers after RRSO is not greater than expected. Hysterectomy is not routinely recommended for these patients.

Vaginal dilator use more than 9 months is a main prognostic factor for reducing G2‑late vaginal complications in 3D‑vaginal‑cuff brachytherapy (interventional radiotherapy)?

Abstract Purpose Analyse the impact of different prognostic factors on G2-late vaginal complications after vaginal brachytherapy (VBT) ± external beam radiotherapy (EBRT) in postoperative endometrial cancer (PEC). Methods One hundred and twenty-six PEC patients treated with VBT ± EBRT were retrospectively analysed considering age, body mass index, applicator diameter, clinical target volume (CTV), use of dilators, chemotherapy and EQD2(α/β=3) at the most exposed 2 cm3 of the CTV as prognostic factors for vaginal complications. Late vaginal complications were evaluated using objective LENT-SOMA criteria. Statistics: descriptive analysis, Chi-square, Fisher and Student tests were applied. Univariate and multivariate analyses were performed with the Baptista–Pike exact method and multiple logistic regression. Results Mean age was 65 years (SD ± 10), and median follow-up was 66 months (8–104). 19/126 patients (15%) showed G2-late vaginal complications, and 107/126 (85%) G0–G1. Univariate analysis showed: CTV ≤ 9 cm3 (p = 0.036), use of dilators < 9 months (p = 0.015), and total ≥ 68 Gy EQD2 received by 2 cm3 of CTV (p = 0.039) were associated with G2-late vaginal toxicity. Multivariate analysis showed the use of dilators < 9 months as an independent prognostic factor for G2-late vaginal toxicity (p = 0.043, OR 8.59, CI 1.59–159.9). Conclusion The use of dilators < 9 months in VBT ± EBRT for PEC was an independent prognostic factor for G2-late vaginal toxicity. The use of vaginal dilators ≥ 9 months requires further analysis in studies evaluating late vaginal toxicity.

Glycosylation and its research progress in endometrial cancer

AbstractEndometrial cancer (EC) is one of the most common tumors in the female reproductive system, which seriously threatens women's health, particularly in developed countries. 13% of the patients with EC have a poor prognosis due to recurrence and metastasis. Therefore, identifying good predictive biomarkers and therapeutic targets is critical to enable the early detection of metastasis and improve the prognosis. For decades, extensive studies had focused on glycans and glycoproteins in the progression of cancer. The types of glycans that are covalently attached to the polypeptide backbone, usually via nitrogen or oxygen linkages, are known as N‑glycans or O‑glycans, respectively. The degree of protein glycosylation and the aberrant changes in the carbohydrate structures have been implicated in the extent of tumorigenesis and reported to play a critical role in regulating tumor invasion, metabolism, and immunity. This review summarizes the essential biological role of glycosylation in EC, with a focus on the recent advances in glycomics and glycosylation markers, highlighting their implications in the diagnosis and treatment of EC.

An effective algorithm to detect the possibility of being MSI phenotype in endometrial cancer given the BMI status and histological subtype: a statistical study

Abstract Purpose In endometrial cancer, the incidence of mutations in mismatch repair genes (MMR) is estimated at 17–30%. Patients with alterations at this level (MSI) are known to have different clinical and anatomopathological characteristics than those without this genetic alteration (MSS). In this study, we aim to identify the MSI phenotype in patients who underwent hysterectomy for endometrial cancer. We assessed the correlation of this phenotype with anatomoclinical parameters such as obesity and histological subtype. Methods/patients Clinical and anatomopathological data were collected from 147 patients diagnosed with endometrial cancer and an immunohistochemical study of MMR system proteins was performed. PMS2 and MSH6 proteins were evaluated as primary screening and subsequent evaluation of MLH1 and MSH6, respectively, if the former were negative. Statistical association between the anatomopathological data and the immunohistochemical result was analyzed. Results and conclusions 22.4% of our patients were MSI phenotype. We obtained statistically significant differences by multivariate analysis between endometrioid subtype and higher FIGO classification grade with MSI phenotype and obesity with MSS phenotype. Given these statistical results, we propose a function for predicting the probability of being MSI phenotype taking into account the histological subtype (endometrioid/non-endometrioid carcinoma) and FIGO grade as well as obesity. This prediction may be useful prior to hysterectomy, for genetic study of the MLH1 promoter and subsequent genetic counseling.

SEOM-GEICO clinical guidelines on endometrial cancer (2021)

AbstractEndometrial cancer (EC) is the second most common gynecological malignancy worldwide, the first in developed countries [Sung et al. in CA Cancer J Clin 71:209–249, 2021]. Although a majority is diagnosed at an early stage with a low risk of relapse, an important proportion of patients will relapse. Better knowledge of molecular abnormalities is crucial to identify high-risk groups in early stages as well as for recurrent or metastatic disease for whom adjuvant treatment must be personalized. The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of EC, and to provide evidence-based recommendations for clinical practice.

Preliminary results of a vaginal constraint for reducing G2 late vaginal complications after postoperative brachytherapy in endometrial cancer: a prospective analysis

Abstract Purpose To evaluate the preliminary results of the use of 68 Gy EQD2(α/β=3 Gy) as a dose limit to the lowest dose in the most exposed 2 cm3 of the vagina in order to reduce G2 late vaginal problems in postoperative endometrial carcinoma (EC). Methods From November 2016 to October 2019, 69 postoperative EC patients receiving vaginal brachytherapy (VBT) ± external beam radiotherapy (EBRT) were prospectively analyzed. The median EBRT dose was 45 Gy (range: 44–50.4 Gy), 1.8−2 Gy/day, 5 fractions(Fr)/week. VBT was administered with the following schedule: 1Fr of 7 Gy after EBRT and 2 daily Fr × 7.5 Gy in exclusive VBT. The dose was prescribed at 0.5 cm from the applicator surface with an active length of 2.5 cm; 56 patients were treated with vaginal cylinders (49–3.5 cm, 6–3 cm, and 1–2.5 cm) and 13 with the colpostat technique. The overall VBT dose was adjusted to meet the vaginal restriction of < 68 Gy EQD2(α/β=3 Gy) at 2 cm3. Late toxicity was prospectively assessed using RTOG scores for bladder and rectum, and the objective LENT-SOMA criteria for vagina. Results With a median follow-up of 31.0 months, no vaginal-cuff recurrences were found. Late toxicity: only 1G1(1.4%) rectal toxicity; 21G1(30.4%) and 3G2(4.3%) vaginal complications. Only one (1.4%) of 3 G2 manifested as vaginal shortening. Conclusions In postoperative EC patients treated with VBT, only one developed G2 vaginal stenosis with the use of 68 Gy EQD2(α/β=3 Gy) as a dose constraint. These preliminary results seem to indicate the value of this dose limit for reducing G2 vaginal stenosis. Nonetheless, these findings should be confirmed in a larger number of patients with longer follow-up.

Impact of TP53 somatic mutations on prognosis in endometrial cancer: a systematic review and meta-analysis

Endometrial cancer (EC) is the sixth most common female cancer and may rank fourth in cancer mortality by 2040. TP53 mutations and aberrant p53 expression are associated to aggressive tumor subtypes and poor prognosis, reducing overall survival (OS), disease-free survival, recurrence rates (RcR) and Mortality Risk (MR). The prognostic impact of TP53 mutations in EC remains unclear. A systematic search was conducted in PubMed, Embase, and the Cochrane Library. Hazard ratios (HR) and Risk Ratios (RR) with 95% confidence intervals (CI) were combined using random-effects models. Analyses were conducted in RStudio (v4.4.1), and heterogeneity was evaluated using the I Twenty-four studies comprising 5462 EC patients were included. TP53 mutations and aberrant p53 expression were associated with poorer outcomes. For OS, TP53 mutations had an HR of 2.27 (95% CI 1.47-3.49) and aberrant p53 had an HR of 5.01 (95% CI 2.44-10.30). For DFS, TP53 mutations had an HR of 4.20 (95% CI 1.79-9.86), while aberrant p53 had an HR of 2.17 (95% CI 1.27-3.72). TP53 mutations also increased RcR (RR: 2.88; 95% CI 2.18-3.80) and MR (RR: 2.33; 95% CI 1.11-4.88). Aberrant p53 showed a non-significant trend for recurrence (RR: 3.54; 95% CI 0.95-13.10). TP53 mutations and abnormal p53 expression in EC patients predict a poorer prognosis, characterized by increased RcR and MR, as well as lower DFS and OS.

SEOM-GEICO Clinical Guidelines on cervical cancer (2023)

AbstractCervical cancer (CC) is the fourth most common cancer and the fourth leading cause of mortality in women worldwide. It is strongly associated with high-risk human papillomavirus infection. High-income countries that have implemented human papillomavirus (HPV) vaccination and screening programs have seen dramatic reductions in CC incidence, while developing countries where these programs are not available continue to experience high rates of CC deaths. In early-stage CC, the primary treatment is surgery or radiotherapy, whereas concurrent chemo-radiotherapy (CRT) remains the conventional approach in locally advanced stages until the upcoming approval of immunotherapy. The incorporation of immunotherapy in combination with chemotherapy (with or without bevacizumab) in first line and as monotherapy in second line after platinum-based chemotherapy, has significantly increased overall survival (OS) in recurrent or metastatic CC. The purpose of this guideline is to summarize the most relevant evidence in the diagnosis, treatment, and follow-up of CC and to provide evidence-based recommendations for clinical practice.

Tumor-associated macrophages and platelets in tumor microenvironment and its potential therapeutic role in ovarian cancer

Ovarian cancer is one of the most lethal cancers among gynecological tumors, with most cases diagnosed at an advanced stage. Despite advancements in medical science, current therapeutic options remain somewhat constrained, leading to a persistently high mortality among patients. The tumor microenvironment (TME) critically drives ovarian cancer progression by orchestrating tumorigenesis, metastasis, and chemoresistance via intercellular crosstalk, metabolic reprogramming, and immunosuppression. Tumor-associated macrophages (TAMs) and platelets are pivotal components of the ovarian cancer immune microenvironment. These components facilitate critical oncogenic processes, including tumor cell dissemination, immune evasion, and chemoresistance. Both TAMs and platelets have emerged as promising therapeutic targets. Furthermore, bidirectional crosstalk between platelets and TAMs dynamically shapes the immunosuppressive TME. This review synthesizes the roles and mechanisms of TAMs and platelets in ovarian cancer progression, discusses emerging therapeutic strategies targeting these components, and establishes a framework for advancing novel therapies in ovarian cancer treatment.

Clinicopathological insights and prognostic implications of DEK in association with apoptosis-regulating factors in ovarian cancer

Ovarian cancer is one of the most common gynecologic malignancies of the present era. Dysregulation of apoptosis is considered as one of the most important factors for malignant transformation. DEK is a ubiquitous protein, and its downregulation induces apoptosis by altering BCL-2, BAX, and CASPASE-3 expressions. This study illuminates the cumulative clinical usefulness of DEK and related apoptotic proteins. A total of 119 patients were enrolled during 2021-2023. Demographic and clinicopathological data were recorded at presentation, and the follow-up was done till August 2024. Tissue samples were analyzed using immunohistochemistry and real-time PCR. A paired t test assessed gene expression between normal and malignant tissues of different treatment strategies. The crosstab was performed to find the association of DEK, BCL-2, BAX, and CASPASE-3 with clinicopathological features. Pearson's correlation was used to predict the association of DEK with other apoptotic factors. Survival and hazard risk were evaluated using log-rank and Cox regression. The mean age of OC patients was 47.61 ± 12.5 years, presented with advanced stage (90.7%) and grade (85.3%). Most of them were post-menopausal (68.08%) and had unhygienic (76.5%) regular menstrual cycles (89.1%), and also experienced early pregnancy (61.8%). Some of these factors are related to a hazard risk (HR > 1). DEK and apoptotic proteins were upregulated in OC than in normal (p ≤ 0.01). DEK was positively correlated with BCL-2, BAX, and CASPASE-3, at both mRNA and protein levels, and only BAX showed significance in both (p ≤ 0.05). All the selected genes are independent risk factors for survival of OC (HR > 1), but only DEK and CASPASE-3 were significantly associated with poor survival (p ≤ 0.05). Dysregulation of DEK, CASPASE-3, and BAX/BCL-2 is associated with poor overall survival. Further, this study highlights the correlation between DEK and key apoptotic regulators, emphasizing the critical role of DEK in OC prognosis.

TP53 mutations and MDM2 polymorphisms in breast and ovarian cancers: amelioration by drugs and natural compounds

Globally, breast and ovarian cancers are major health concerns in women and account for significantly high cancer-related mortality rates. Dysregulations and mutations in genes like TP53, BRCA1/2, KRAS and PTEN increase susceptibility towards cancer. Here, we discuss the impact of mutations in the key regulatory gene, TP53 and polymorphisms in its negative regulator MDM2 which are reported to accelerate cancer progression. Missense mutations, null mutations, transversions, transitions, and point mutations occurring in the TP53 gene can cause an increase in metastatic activity. This review discusses mutations occurring in exon regions of TP53, polymorphisms in MDM2 and their interaction with large ribosomal subunit protein (RPL) leading to cancer development. We also highlight the potential of small molecules e.g. p53 activators like XI-011, Tenovin-1, and Nutlin-3a for the treatment of breast and ovarian cancers. The therapeutic efficacy of natural compounds in amelioration of these two types of cancers is also discussed.

Open-label phase II clinical trial of orteronel (TAK-700) in metastatic or advanced non-resectable granulosa cell ovarian tumors: the Greko II study (GETHI2013-01)

Granulosa cell ovarian tumors (GCTs) are a rare neoplasia characterized by a pathognomonic mutation in the FOXL2 gene. In vitro studies have demonstrated an overactivation of hormone activity due to this alteration. Thus, we aimed to determine the activity of orteronel, a CYP17 inhibitor, in advanced disease. We designed a multicentric open-label phase II clinical trial. Eligible patients were adult woman with advanced or unresectable GCTs. Primary objective was clinical benefit rate, defined as the average of patients with radiological response plus stable disease longer than 6 months. From October 1, 2014 to May 20, 2016, ten patients were included in six participating institutions members of the GETTHI group. The study was terminated early due to a low recruitment rate. Up to 40% (CI 95% [9.6-70.4%]) cases presented a disease stabilization longer than 6 months and two of them, longer than 12 months. One patient continued on treatment at database closure 29 months after inclusion in the trial. No patient reached partial or complete response by RECIST criteria on the independent radiological review. The drug was well tolerated with nausea as the only grade 3 adverse event in one case. Low accrual led to an early interruption of the study. However, orteronel achieved a promising clinical benefit rate that supports further development of new hormonotherapies in this tumor. NCT02101684.

Decoding β-catenin expression patterns in ovarian serous carcinoma with clinicopathological implications: insights from National Cancer Institute

This study aimed to examine the immunohistochemical expression of β-catenin in serous ovarian carcinoma and to investigate its relationship with clinicopathological features and disease outcomes. A retrospective analysis was conducted on 67 cases of serous ovarian carcinoma diagnosed at the Pathology Department of the Egyptian National Cancer Institute, Cairo University, between January 1, 2015, and December 31, 2017. The age of the patients ranged from 26 to 76 years. Aberrant β-catenin expression was defined by the presence of cytoplasmic staining with or without membranous staining in at least 10% of tumor cells. Of the cases analyzed, thirty exhibited cytoplasmic staining, 18 demonstrated preserved expression on the cell membrane, 15 showed combined cytoplasmic and membranous staining, while four cases were entirely negative. Significant correlations were observed between β-catenin positivity and both tumor grade and p53 expression, with p values of 0.004 for each correlation. Positive β-catenin expression significantly correlated with tumor grade in serous ovarian carcinoma. Most low-grade serous carcinoma cases exhibited membranous β-catenin expression, whereas high-grade serous carcinoma cases predominantly displayed cytoplasmic staining. Therapeutic strategies aimed at inhibiting β-catenin signaling could provide a novel approach to improving outcomes for patients with high-grade ovarian cancer.

Functional and therapeutic significant of heat-shock protein 90 (HSP90) in reproductive cancers

Reproductive cancers, such as ovarian, cervical, and endometrial carcinomas, have a poor prognosis in metastatic stages. Researchers are continuously seeking improved and safer methods to target cancer-related oncoproteins, addressing the limitations of current treatments, including their limited effectiveness, drug resistance, and off-target effects. Recent advancements in understanding the molecular mechanisms involved in the progress of reproductive cancers have provided valuable insights into potential targeted therapies. By engaging with oncoproteins and co-chaperones, heat-shock protein 90 (HSP90) regulates signaling networks and fixes protein folding errors in cancer cells. The potential of HSP90 inhibition as cancer-targeted treatments is underscored by the continuous discovery and testing of novel HSP90-targeted molecules for their antitumor properties in preclinical and clinical settings. Therefore, this study aims to shed light on the mechanism and recent research breakthroughs of HSP90, as well as provide an in-depth review of their therapeutic potential in reproductive cancers.

The sequestosome 1 protein: therapeutic vulnerabilities in ovarian cancer

Ovarian cancer (OC) is the most deadly tumor that may develop in a woman's reproductive system. It is also one of the most common causes of death among those who have been diagnosed with cancer in women. An adapter protein known as sequestosome 1(SQSTM1) or p62 is primarily responsible for the transportation, degradation, and destruction of a wide variety of proteins. This adapter protein works in conjunction with the autophagy process as well as the ubiquitin proteasome degradation pathway. In addition, the ability of SQSTM1 to interact with multiple binding partners link SQSTM1 to various pathways in the context of antioxidant defense system and inflammation. In this review, we outline the processes underlying the control that SQSTM1 has on these pathways and how their dysregulation contributes to the development of OC. At the final, the therapeutic approaches based on SQSTM1 targeting have been discussed.

First-line carboplatin/nab-paclitaxel in advanced ovarian cancer patients, after hypersensitivity reaction to solvent-based taxanes: a single-institution experience

One of the major challenges related to solvent-based taxanes administration in clinical practice is the high rate of hypersensitivity reactions (HSRs). Nab-paclitaxel is a solvent-free, albumin-bound, paclitaxel, which minimize the risk of HSR occurrence. In this single-institution, retrospective analysis, we evaluated stage IIIc-IV epithelial ovarian cancer (EOC) patients, treated with first-line carboplatin/nab-paclitaxel (± bevacizumab), after the occurrence of an HSR with solvent-based paclitaxel (and/or docetaxel). Between April 2012 and December 2018, ten patients (20.8%) received carboplatin/nab-paclitaxel (± bevacizumab) after the occurrence of an HSR to solvent-based taxanes. Among the evaluable patients, ORR was 100%. At median follow-up of 28.5 months, median PFS was 16.7 months, and median OS was 65.4 months, respectively. Median received dose intensity (DI) was 86% and 80% of the projected DI for nab-paclitaxel and carboplatin, respectively. There were no treatment-related grade 4 adverse events. Most relevant treatment-related grade 3 adverse events were: asthenia (10%), hypertransaminasemia (10%), neutropenia (20%), thrombocytopenia (20%), and anemia (10%). No HSR recurrence was observed. The high rate of HSR occurrence could limit first-line treatment options in clinical practice. Carboplatin/nab-paclitaxel association could represent a valid treatment option in this setting.

Venous thromboembolism incidence in cancer patients with germline BRCA mutations

Germline BRCA (gBRCA) mutations predispose to an increased risk of breast and ovarian cancer among other neoplasms. Recently, several genomic alterations such as ALK and ROS-1 rearrangements have been described as molecular drivers of venous thromboembolism (VTE). The association of gBRCA mutations and VTE is unknown. We performed an observational, retrospective, single-center study to determine the VTE incidence in consecutive patients with gBRCA mutations and cancer diagnosis attended in the multidisciplinary heredofamiliar cancer unit (HFCU) of Hospital General Universitario Gregorio Marañón, Spain, from 2010 to 2019. One-hundred and forty-one patients were included in the analysis. The overall VTE incidence was 12.8%. The highest incidence was reported in ovarian cancer patients (20.0%), followed by patients with both ovarian and breast cancers (16.6%) and the lowest was found in breast cancer (4.9%). No difference in the type of gBRCA mutation (1 or 2) in terms of VTE rate was observed. Sixty one percent of the patients were receiving anti-cancer therapy at the time of VTE diagnosis and the majority of the events (83.3%) were diagnosed in ambulatory setting. Khorana score was of limited value to detect high-risk patients. The VTE incidence observed in our study is consistent with prior data described in general population of breast and ovarian cancer. The risk of VTE in these patients seems to be driven by the type of cancer. We have not observed any significant interaction of gBRCA mutation status and cancer-associated thrombosis.

Review of biomarker systems as an alternative for early diagnosis of ovarian carcinoma

Early diagnosis of ovarian carcinoma is bound to boost the long-term endurance rate of the patients. Most ovarian tumors happen post menopause when the ovaries have no vital operation and therefore irregular ovarian role causes no signs. According to Muinao T. et al. (Heliyon. 5(12):e02826, 2019), if we consider the frequency of ovarian carcinoma to be moderate, a screening technique must accomplish a base specificity of 99.6% and sensitivity of over 75%. The classification and approval of early diagnostic biomarkers explicit to ovarian carcinoma are essentially required. Prevailing methods for early diagnosis of ovarian carcinoma incorporate TVS, biological marker examination, or a blend of the two or other. In recent years, it has been revealed that a combination of at least two biomarkers has beaten single biomarkers in measures for early diagnosis of the illness. In the present document, we survey the ongoing exploration of innovative characteristic methodologies and possible panels of carcinoma biological markers for the early diagnosis of ovarian carcinoma and discuss biomarkers as the plausible apparatus for model improvement and other progressed approaches as an effective alternative to the prevailing methods for early diagnosis of this dreadful disease to evade bogus analysis and inordinate expense.

The multifaced role and therapeutic regulation of autophagy in ovarian cancer

Ovarian cancer (OC) is one of the tumors that occurs most frequently in women. Autophagy is involved in cell homeostasis, biomolecule recycling, and survival, making it a potential target for anti-tumor drugs. It is worth noting that growing evidence reveals a close link between autophagy and OC. In the context of OC, autophagy demonstrates activity as both a tumor suppressor and a tumor promoter, depending on the context. Autophagy's exact function in OC is greatly reliant on the tumor microenvironment (TME) and other conditions, such as hypoxia, nutritional deficiency, chemotherapy, and so on. However, what can be concluded from different studies is that autophagy-related signaling pathways, especially PI3K/AKT/mTOR axis, increase in advanced stages and malignant phenotype of the disease reduces autophagy and ultimately leads to tumor progression. This study sought to present a thorough understanding of the role of autophagy-related signaling pathways in OC and existing therapies targeting these signaling pathways.

High expression of CETN2 is associated with platinum resistance and poor prognosis in epithelial ovarian cancer

The poor prognosis of ovarian cancer is largely due to platinum resistance. It has been demonstrated that nucleotide excision repair (NER) involving centrin-2(CETN2) is connected to platinum resistance in ovarian cancer. The molecular mechanism of CETN2 in ovarian cancer and the mechanism affecting the outcome of chemotherapy are unknown. The protein-protein interaction (PPI) network was mapped after obtaining the interacting proteins of CETN2, and the interacting genes were subjected to enrichment analysis. To examine the relationship between CETN2 and platinum resistance, gene microarray data and clinical data related to platinum resistance in ovarian cancer were downloaded. The possible signaling pathway of CETN2 was investigated by Gene set enrichment analysis (GSEA). Immune infiltration analysis was performed. Immunohistochemistry (IHC) and quantitative real-time PCR (QRT-PCR) were used to examine the expression of CETN2 in clinical samples in relation to the effectiveness of chemotherapy. The capacity of CETN2 to predict chemotherapy results was proven by receiver operating characteristic (ROC) curves after the construction of two prediction models, the logistic regression model and the decision tree model. The impact of CETN2 on prognosis was examined using the Kaplan-Meier technique. CETN2 was associated with NER, oxidative phosphorylation (OXPHOS) and cell cycle pathways in ovarian cancer drug-resistant samples. In clinical samples, CETN2 showed its possible correlation with immune infiltration. The protein expression level of CETN2 was significantly higher in platinum-resistant patients than that in platinum-sensitive patients, and the expression level had some predictive value for chemotherapy outcome, and high CETN2 protein expression was associated with poorer progression-free survival. CETN2 protein had a significant effect on ovarian cancer platinum sensitivity and prognosis, which may be related to the activation of NER, OXPHOS and cell cycle pathways upon CETN2 upregulation. Further research is necessary to determine the therapeutic application value of CETN2, which may be a new biomarker of chemoresponsiveness.

IL-6 secretion of CD4+ T cells stimulated by LC3-positive extracellular vesicles in human epithelial ovarian cancer

Ovarian cancer (OC) as the most fatal gynecological malignancy worldwide, with epithelial ovarian cancer (EOC) being the predominant and most lethal form, poses a serious threat to human health. LC3-positive extracellular vesicles (LC3

Outcomes of vaginal squamous cell carcinoma of patients treated with radiation therapy: a series of 37 patients from a single expert center

The aim is to assess the outcome of patients treated for vaginal carcinoma with radiation therapy in terms of long-term tolerance and survival. This single-center retrospective study included patients with squamous cell carcinoma of the vagina treated with pelvic external beam radiation therapy (EBRT) with or without vaginal brachytherapy (VB) between 1990 and 2013. Thirty-seven patients were included with stage I (24%), II (60%), III (8%), or IV (8%) vaginal tumors. Median age was 66 years (range 27-86 years). Median tumor size was 4 cm (range 0.7-12 cm). Seven patients underwent first intention surgery. The 37 patients received pelvic EBRT (45 Gy) with inguinal irradiation in 57% of cases. Fifteen (41%) received concurrent chemotherapy. Low-dose supplemental VB was performed in 31 patients (84%) (median dose: 20 Gy). Median follow-up was 59 months (range 7-322 months). Four patients (11%) had late grade 3-4 complications. Relapse occurred in 11 patients (30%), five of them locally. The 5-year relapse-free and cancer-specific survival rates were 68% and 76%, respectively. Surgery and concurrent chemotherapy did not seem to have an impact on the course of the disease. In our experience, pelvic EBRT leads to prolonged survival with acceptable long-term toxicity in patients with squamous cell carcinoma of the vagina.

The role of the inflammasome and its related pathways in ovarian cancer

Ovarian cancer (OC) is the most lethal tumor of the female reproductive tract and one of the most prevalent causes of death among female cancer patients. The absence of suitable procedures for early diagnosis, chemoresistance, and limited surgical debulking are all contributing to poor survival in patients. Despite aggressive treatments, the majority of patients have a recurrence within 16-22 months. Inflammasomes are multimeric protein complexes that play a major role in the innate immune system and inflammation. The overexpression of inflammasome-related pathways, including NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), Absent in melanoma 2 (AIM2), caspase-1, and Interleukin (IL)-1 have been reported in OC patients and in vitro cell lines. Therefore, inflammasome-related genes and protein might have a role in OC pathogenesis. Considering the potential relationship between inflammasome and OC, this study aimed to provide a literature-based review to explain the role of inflammasome and inflammation in cancer progression in OC.

Interval cytoredutive surgery and HIPEC in advanced ovarian cancer with small-bowel disease: results and reflections

Small-bowel involvement in patients with ovarian cancer has been strongly correlated with the possibility of cytoreduction and thus with survival. The main objective of this study was to evaluate the prognostic significance of small-bowel involvement in patients undergoing optimal-complete interval cytoreductive surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC). We included a series of patients diagnosed with stage IIIC-IVA (pleural effusion) high-grade serous epithelial ovarian cancer and in whom CRS + HIPEC was indicated after neoadjuvant systemic chemotherapy (NACT). The study period extended from January 2008 to January 2020, with a minimum follow-up of 12 months from the inclusion of the last patient. A multivariate analysis using Cox regression allowed us to identify the variables that were independently related to disease-free survival. A total of 144 patients were selected, 13 (9%) of whom were excluded from the analysis, because their disease was considered unresectable. The study included a series of 131 patients with a median age of 62 years (34-79 years) and a median Peritoneal Cancer Index (PCI) calculated during surgery of 9 (1-35). The median PCI of bowel areas 9-12 (SB-PCI) was 3 (1-10). Performance of a CC-1 cytoreduction (HR: 1.93, 95% CI: 1.02-3.64, p = 0.042) and SB-PCI greater than 3 (HR: 2.25, 95%CI: 1.13-4.48, p = 0.21) were independent factors associated with shorter disease-free survival. Small-bowel involvement, even in patients with a macroscopically complete resection, showed a correlation with worse prognostic outcomes and could be considered as a variable in the postoperative management of these patients.

CDKN2A inhibits cell proliferation and invasion in cervical cancer through LDHA-mediated AKT/mTOR pathway

The current study aims to explore the effects of CDKN2A on cell proliferation and cycle, and investigate the underlying mechanisms. Expression of CDKN2A in cervical cancer cell lines was evaluated by real-time quantitative PCR (RT-qPCR) and western blotting. Apoptotic rate was detected by Annexin V assay. MTT assay, Transwell assay and cell cycle assay kit were applied to examine the effect of CDKN2A on cell viability, invasion and cell cycle. Co-immunoprecipitation and western blotting were devoted to explore the mechanism by which CDKN2A contributes to cell function. CDKN2A was expressed at a low level in cervical cancer cell lines. Overexpression of CDKN2A inhibited cell proliferation and invasion, and caused cell cycle arrest in the G1 phase. CDKN2A mediates the AKT-mTOR signaling pathway by suppressing lactate dehydrogenase (LDHA). Taken together, our data revealed that CDKN2A can be applied as a therapeutic target for the treatment of cervical cancer in future. CDKN2A inhibits cell proliferation and invasion in cervical cancer through LDHA-mediated AKT-mTOR pathway.

The application value of PAX1 and ZNF582 gene methylation in high grade intraepithelial lesion and cervical cancer

To investigate the possibility of using the methylation level of PAX1/ZNF582 gene as molecular marker to differentiate the progression of cervical cancer. From January 2016 to March 2018, 150 patients, who were admitted to Cervical Disease Diagnosis and Treatment Center of Xuzhu Maternity and Child Care Hospital, were enrolled in this study. Patients were classified into chronic cervicitis (for 19 cases), low-grade squamous intraepithelial lesion (LSIL) (18 cases), high-grade squamous intraepithelial lesion (HSIL) (37 cases) and squamous cell carcinoma (SCC) (31 cases). All patients underwent several tests including Thin-prep cytology test (TCT), HPV DNA detection and detection of methylation level of PAX1/ZNF582 genes. For diagnosis of HSIL, the area under curve (AUC) was 0.878 (95% CI 0.806 ~ 0.950); the threshold for PAX1 was 12.285, the sensitivity and specificity were 91.9% and 72.8%, respectively. The AUC of ZNF582 gene detection was 0.900 (95% CI 0.842 ~ 0.959), the threshold was 11.56, while the sensitivity and specificity were 97.3% and 76.7%, respectively. Among various tests we conducted, PAX gene detection methods showed the highest specificity (97.30%). PAX1/ZNF582 gene detection method demonstrated the highest accuracy. For patients with high-grade cervical lesion and cervical cancer, the methylation level of PAX1/ZNF582 gene could be applied as a noteworthy biomarker for diagnosis and for cervical cancer classification.

Synergistic anti-tumor effect of paclitaxel and miR-34a combined with ultrasound microbubbles on cervical cancer in vivo and in vitro

Improved therapeutic options for cervical cancer are needed. The purpose of this study was to evaluate the synergetic, inhibitory effects of ultrasound-mediated paclitaxel (PTX)- and miR-34a-loaded microbubbles (MBs) on cervical cancer. U14 cervical cancer cells and xenograft mouse tumors were treated with PTX-miR-34a-MBs. Levels of miR-34a increased in vitro and vivo after treatment with ultrasound-mediated PTX-miR-34a-MBs. Furthermore, this treatment decreased the proliferation of cervical cancer cells, microvessel density, and the expression of Bcl-2 and CDK6, both in vitro and in vivo. Furthermore, Bax expression was increased in the in vivo model. And, tumor volume and weight were significantly reduced by 78.57% and 87.97%, respectively (P < 0.01). These results indicate that ultrasound-mediated PTX-miR-34a-MBs synergistically inhibit the growth of cervical cancer via the upregulation of miR-34a and downregulation of Bcl-2 and CDK6. Thus, PTX-miR-34a-MBs in combination with ultrasound microbubbles are a promising anticancer delivery strategy for treating cervical cancer.

The role of brachytherapy (interventional radiotherapy) for primary and/or recurrent vulvar cancer: a Gemelli Vul.Can multidisciplinary team systematic review

The aim of our systematic review was to assess the role of interventional radiotherapy (IRT, brachytherapy) in the management of primary and/or recurrent vulvar carcinoma. A systematic research using PubMed, Scopus and Cochrane library was performed. ClinicalTrials.gov was searched for ongoing or recently completed trials, and PROSPERO was searched for ongoing or recently completed systematic reviews. Only full-text English-language articles related to IRT for treatment of primary or recurrent VC were identified and reviewed. Conference paper, survey, letter, editorial, book chapter and review were excluded. Time restriction (1990-2018) as concerns the years of the publication was considered. Primary disease: the median 5-year LC was 43.5% (range 19-68%); the median 5-year DFS was 44.5% (range 44-81%); the median 5-year OS was 50.5% (range 27-85%). Recurrent disease: the median 5-year DFS was 64% (range 56-72%) and the median 5-year OS was 45% (range 33%-57%). Acute ≥ grade 2 toxicity was reported in three patients (1.6%). The severe late toxicity rates (grade 3-4) ranged from 0% to 14.3% (median 7.7%). IRT as part of primary treatment for primary and/or recurrent vulvar cancer is associated with promising clinical outcomes.

MiR-495-3p and miR-143-3p co-target CDK1 to inhibit the development of cervical cancer

The GEO database and KEGG database-based analyses identified the differential expression of cyclin-dependent kinase 1 (CDK1) in cervical cancer and its involvement in the cell cycle pathway. In the present study, we aim to clarify the role of CDK1 in cervical cancer and the function of upstream microRNA (miR)-143-3p/miR-495-3p. The expression of miR-143-3p, miR-495-3p, and CDK1 in cervical cancer tissues and cells was determined using RT-qPCR. Cell bioactivities were examined by CCK-8 and flow cytometry. The binding affinity between CDK1 and miR-143-3p/miR-495-3p was investigated using dual luciferase gene reporter assay. A xenograft mouse model of cervical cancer was then established to explore their effect on the tumorigenicity of cervical cancer cells in vivo. CDK1 was found to be the common target gene of miR-143-3p and miR-495-3p. CDK1 overexpression occurred in cervical cancer tissues and cells, while expression of miR-495-3p and miR-143-3p was down-regulated. The viability was inhibited while the apoptosis was promoted in cervical cancer cells in response to miR-143-3p or miR-495-3p overexpression, or CDK1 silencing. Further, miR-143-3p or miR-495-3p overexpression was also substantiated to inhibit the tumorigenicity of cervical cancer cells in vivo, while CDK1 overexpression counteracted their effect. Taken together, miR-143-3p and miR-495-3p co-target CDK1, thereby inhibiting the occurrence and development of cervical cancer.

Immune infiltration could predict the efficacy of short-term radiotherapy in patients with cervical cancer

Radiotherapy is the main treatment for cervical cancer. It is usually applied alone or in combination with surgery and/or chemotherapy. To explore the association between immune microenvironment of cervical cancer and radiotherapy response, we collected 20 paired cervical cancer tumor samples before and after radiotherapy and partial clinical information. With paired-end RNA-seq, we quantified the immune infiltration and tumor purity of these samples, and obtained 6350 differentially expressed genes before and after radiotherapy. With the help of R language, the function enrichment analysis and 22 immune cells infiltration analysis were carried out. Moreover, we built a random forest model based on the immune microenvironment to predict the short-term efficacy of radiotherapy. We found that the effect of radiotherapy on the immune microenvironment of stage III and IV cervical cancer patients was weaker than that of stage I and II cervical cancer patients. Radiotherapy can significantly reduce the tumor purity and increase immune infiltration. The proportions of the immune infiltrating cells are predictive of the radiotherapy efficacy. In addition, the local mucositis caused by radiotherapy can improve the curative effect of radiotherapy.

Multiparametric immune profiling of advanced cervical cancer to predict response to programmed death-1 inhibitor combination therapy: an exploratory study of the CLAP trial

Checkpoint immunotherapy is a promising treatment option for advanced cervical cancer. To aid in selecting patients for this treatment, we identified potential predictors of the response to anti-PD-1 combination therapy. We simultaneously characterized CD8 CD8 Multiparametric immune profiling of CD8 ClinicalTrials. gov identifier: NCT03816553, January 25, 2019.

Adjuvant therapy in early-stage cervical cancer after radical hysterectomy: are we overtreating our patients? A meta-analysis

There is a gap in knowledge regarding the ideal management of patients with early-stage cervical cancer and intermediate-risk features. Here, we present a meta-analysis of the published literature on oncological outcomes in these patients and determine trends in postoperative management. MEDLINE and PubMed were used for literature searches. The inclusion criteria were: English language articles including ≥ 10 patients, patients who underwent radical hysterectomy, nodes negative, studies reporting oncological outcomes and complications treatment-related and compare a surgery-only cohort with a radiotherapy cohort. The PRISMA guidelines were followed. Combined relative risk was calculated using DerSimonian-Laird random-effects model and a forest plot was drawn. We collected 183 manuscripts on early-stage cervical cancer treated with radical hysterectomy alone or with adjuvant radiotherapy after surgery. A total of eight studies met the inclusion criteria. Regarding oncological outcomes, survival was reported in five studies. The relative risk of recurrence and the relative risk of mortality was similar in both groups independently whether receive or not adjuvant therapy. Most of the studies did not report significant differences regarding morbidity treatment related between the groups, except for a higher rate of lymphedema after radiotherapy. We found that the relative risk of recurrence and mortality was similar in both groups not depending on adjuvant therapy. Therefore, whether radiotherapy adjuvant treatment is indicated remains a topic of debate.

Identification of a novel hypermethylation marker, ZSCAN18, and construction of a diagnostic model in cervical cancer

Cervical cancer (CC), a common female malignancy, has been linked to alterations in DNA methylation. This study employed an integrated "dry-wet lab" strategy combining bioinformatics, machine learning, and experimental validation to identify novel methylation biomarkers for CC. Methylome and transcriptome data from the TCGA and GEO cohorts (n=349 discovery, n=414 validation) were analyzed to identify differentially methylated CpGs. The top candidates were validated by pyrosequencing, methylation-specific PCR, and quantitative assays. Diagnostic models were developed, and functional studies were performed for the target markers. Eighteen differentially methylated CpGs were identified, with five top candidates (three in the ZSCAN18 promoter) showing diagnostic potential. ZSCAN18 promoter methylation levels and positivity rates were significantly greater in CC tissues than in normal tissues (p<0.05), reaching 77.8% (21/27) in ThinPrep cytology test (TCT) samples. The ridge regression diagnostic model achieved an AUC of 0.9421 in the validation cohort. Similarly, ZSCAN18 overexpression suppressed CC cell proliferation (p<0.05). This study established a rapid, effective and systematic systemic research strategy to screen novel methylation markers for CC. ZSCAN18 promoter methylation correlates with cervical lesion severity, and the diagnostic model enhances the diagnostic ability. These findings highlight the dual role of ZSCAN18 as a diagnostic marker and potential therapeutic target.

Study on the mechanism of let-7a-5p in regulating the proliferation in cervical cancer cells

To explore the regulatory effect of let-7a-5p/TGFBR1/Smad3 on the proliferation activity of cervical cancer cells. The difference in let-7a-5p expression between normal people and patients with cervical cancer was detected by miREIA assay. The differences of let-7a-5p expression between cervical cancer cell line C33a and adjacent normal epithelial cell line HUCEC were determined by qRT-PCR. miREIA result showed that let-7a-5p concentrations were 178.5 ± 24.3 μg/L in healthy individuals and 106.1 ± 14.8 μg/L in cervical cancer patients (P = 0.0002). qRT-PCR showed that let-7a-5p in cervical cancer tissue (0.57 ± 0.03) was lower than that in adjacent normal tissue (0.84 ± 0.04, P = 0.0107). Compared with normal cervical epithelial cells (HUCEC), the expression of let-7a-5p was lower in cervical cancer cells (C33a, Hela, P = 0.0001). The results of CCK-8 and EDU detection showed that activation of let-7a-5p inhibited the proliferation of C33a (P = 0.00130, P << 0.0001) and Hela (P = 0.00254, P = 0.0066) cells. According to the analysis using Starbase V2.0 online database, let-7a-5p could target TGFβR1 in cervical cancer cell lines, and the let-7a-5p mimic reduces the mRNA expression level of TGFβR1 in cervical cancer cell C33a (P = 0.0067). Western blot results showed that TGFBR1 expression significantly decreased in cervical cancer cells after let-7a-5p mimic treatment (P = 0.0048) and significantly increased after let-7a-5p mimic inhibitor treatment (P = 0.0003). let-7a-5p represents the independent novel anti-oncogenes in cervical cancer, which can regulate TGF-β1/TGFBR1/pSmad3 cell pathway and interfere with the proliferation of cervical cancer cells. Therefore, let-7a-5p can serve as a novel potential therapeutic target for the treatment of cervical cancer.

RNA modification “writer”-mediated RNA modification patterns and tumor microenvironment characteristics of cervical cancer

As an epigenetic regulation mechanism after transcription, RNA modification is installed by endogenous "writer" enzymes and is widely involved in a variety of physiological processes, including cancer progression. This study explored the RNA modification patterns of cervical cancer to clarify overall effect of RNA modification on tumor microenvironment (TME) characteristics and immune/targeted therapy. 26 RNA modification "writers" were clustered, and the RNA modification patterns and TME characteristics of cervical cancer patients in TCGA were systematically evaluated. Based on differentially expressed genes (DEGs) between different RNA modification patterns, an RNA modification "writer" score (WM score) system was developed to assess the RNA modification of a single sample. Two different RNA modification patterns of cervical cancer were identified, and these patterns were significantly related to the prognosis and TME infiltration characteristics of patients. WM score was an independent risk factor for the prognosis of cervical cancer. High WM score was characterized by poor prognosis, low immune infiltration and low tumor mutation burden (TMB), while low-WM score was related to relatively long overall survival (OS), more immune components in TME and increased TMB. In addition, the low-WM score group was expected to be more sensitive to programmed cell death protein 1 (PD-1) therapy and showed lower predicted IC This study identified and characterized RNA modification patterns, and clarified potential relationship between RNA modification patterns and immune infiltration characteristics and immunotherapy of cervical cancer, offering a new evaluation scheme for treatment of cervical cancer patients.

Real-world incidence and risk of myelodysplastic syndrome and acute myeloid leukemia secondary to PARP inhibitors in ovarian cancer

LncRNAs signatures in gynecological cancers: ovarian and endometrial cancers

Ovarian and endometrial cancers rank among the most common and deadliest cancers affecting women globally. One of the most important factors that impacts patient survival is how early the tumor is detected. Unfortunately, these cancers often present vague symptoms that usually don't show up until the disease is already in an advanced stage. This makes early diagnosis and screening quite difficult. As a result, researchers are actively seeking better diagnostic tools and treatment approaches. In recent years, non-coding RNAs (ncRNAs) have gained significant attention for their key roles in controlling various cellular activities, especially in cancer. Among them, long non-coding RNAs (lncRNAs) are being explored for their potential as therapeutic targets, as well as their usefulness as diagnostic markers and indicators of poor outcomes. This article focuses on how lncRNAs could be crucial in driving or suppressing cell growth, invasion, metastasis, cell death, and resistance to drugs in ovarian and endometrial cancers.

Peritoneal cancer index in ovarian cancer: what does the surgeon really see?

The aim of this paper is to study the agreement between the findings described by the surgeon during surgery (surgical Peritoneal Cancer Index or sPCI) and those obtained after the histopathological analysis (pathological Peritoneal Cancer Index or pPCI) of the resection specimens, in addition to their prognostic implications. A consecutive series of patients diagnosed with high-grade serous ovarian cancer with peritoneal dissemination was analyzed between January 2008 and December 2022. sPCI were correlated with the pPCI results. The study considered the surgeon as a diagnostic tool and established, in ovarian cancer, the parameters of sensitivity, specificity, predictive values, and probability coefficients. Specifically, the study focused on the subgroup of patients with false-positive results from sPCI compared to pPCI and its usefulness in assessing the prognosis of the disease. A total of 231 patients were included, evaluating a total of 3003 peritoneal areas. The median sPCI was 9 (range: 0-35) and 7 for pPCI. Of the 3,003 peritoneal areas evaluated, 132 areas were considered false positives for sPCI. After multivariate analysis, the location of the lesions in the supramesocolic compartment (OR 2.37, 95% CI 1.19-4.53, p = 0.014) was the only independent factor related to a false-positive sPCI result. Patients with false-positive sPCI had a better disease-free survival estimate. The main usefulness of pPCI would be determined by its ability to correct prognostic estimates of the disease, especially in the case of false positives.

Causal inference in the diagnosis and prognosis of ovarian cancer: current state and future directions

Ovarian cancer represents one of the most lethal gynecologic malignancies, characterized by low early detection rates and challenging prognostic assessment. Conventional diagnostic modalities demonstrate limited sensitivity and specificity for early-stage disease identification. Recent research has begun to explore causal inference methodologies as complementary approaches that may enhance diagnostic precision and prognostic capability. This systematic review evaluates the current state and future prospects of causal inference methodologies in enhancing ovarian cancer diagnosis and prognosis. We performed a comprehensive systematic review focusing on causal inference methodologies applied to ovarian cancer research. The analysis encompassed biomarker identification, pathogenic mechanism elucidation, and multimodal data integration. Additionally, we analyzed the synergistic combination of causal inference with machine learning approaches across genomic, transcriptomic, proteomic, and imaging datasets. Causal inference methods have shown effectiveness in identifying crucial biomarkers and revealing underlying pathogenic mechanisms of ovarian cancer. The integration of machine learning with causal inference has enhanced model interpretability, clinical applicability, and diagnostic-prognostic accuracy. These approaches have achieved improved predictions of disease progression and optimization of treatment strategies by leveraging clinical, genetic, and imaging data. Causal inference shows considerable potential in advancing precision medicine for ovarian cancer, offering robust frameworks for addressing confounding factors and establishing causal relationships. As these methodologies evolve and data volumes expand, their application may become increasingly valuable in oncology practice.

BRCA1/2 methylation and expression dynamics in hereditary breast and ovarian cancer: insights from gene, protein, and TCGA analysis

BRCA1/2 Mutations have been linked to an inherited risk of breast and ovarian cancer. However, gene silencing by promoter methylation of BRCA1 and BRCA2 has not been studied extensively. Promoter methylation of BRCA1 and BRCA2 in the gDNA of 113 hereditary breast and ovarian cancer patients was carried out using methylation-specific qPCR. The majority of patients showed higher methylation in BRCA2 than in BRCA1 and were significantly associated with hereditary breast and ovarian cancer Moreover, BRCA2 methylation was significantly associated with BRCA2 downregulation. Additionally, protein expression analysis in a subset of 25 patients with hypermethylated demonstrated a significant negative correlation between methylation status and protein expression for both BRCA1 and BRCA2. BRCA1 and BRCA2 promoter methylation, particularly BRCA2, contributes to gene silencing and protein loss, and may act as key biomarkers for hereditary breast and ovarian cancer prognosis and therapy.

Clinical implications of epithelial-to-mesenchymal transition in cancers which potentially spread to peritoneum

Emerging biologic and clinical implications of miR-182-5p in gynecologic cancers

Single-cell RNA sequencing and cell–cell communication analysis reveal tumor microenvironment associated with chemotherapy responsiveness in ovarian cancer

To investigate the impact of the tumor microenvironment (TME) on the responsiveness to chemotherapy in ovarian cancer (OV). We integrated single cell RNA-seq datasets of OV containing chemo-response information, and characterize their clusters based on different TME sections. We focus on analyzing cell-cell communication to elaborate on the mechanisms by which different components of the TME directly influence the chemo-response of tumor cells. scRNA-seq datasets were annotated according to specific markers for different cell types. Differential analysis of malignant epithelial cells revealed that chemoresistance was associated with the TME. Notably, distinct TME components exhibited varying effects on chemoresistance. Enriched SPP1 Our study indicates that the non-tumor cell components of the TME (e.g. SPP1

PPM1F regulates ovarian cancer progression by affecting the dephosphorylation of ITGB1

PPM1F has been shown to play diverse biological functions in the progression of multiple tumors. PPM1F controls the T788/T789 phosphorylation switch of ITGB1 and regulates integrin activity. However, the impacts of PPM1F and ITGB1 on ovarian cancer (OV) progression remain unclear. Whether there is such a regulatory relationship between PPM1F and ITGB1 in ovarian cancer has not been studied. Therefore, the purpose of this study is to elucidate the function and the mechanism of PPM1F in ovarian cancer. The expression level and the survival curve of PPM1F were analyzed by databases. Gain of function and loss of function were applied to explore the function of PPM1F in ovarian cancer. A tumor formation assay in nude mice showed that knockdown of PPM1F inhibited tumor formation. We tested the effect of PPM1F on ITGB1 dephosphorylation in ovarian cancer cells by co-immunoprecipitation and western blotting. Loss of function was applied to investigate the function of ITGB1 in ovarian cancer. ITGB1-mut overexpression promotes the progression of ovarian cancer. Rescue assays showed the promoting effect of ITGB1-wt on ovarian cancer is attenuated due to the dephosphorylation of ITGB1-wt by PPM1F. PPM1F and ITGB1 play an oncogene function in ovarian cancer. PPM1F regulates the phosphorylation of ITGB1, which affects the occurrence and development of ovarian cancer.

First-line PARP inhibitor maintenance treatment in ovarian carcinoma for older adult women: a review of the current literature

Ovarian cancer (OC) is the leading cause of death in women with gynecological cancers. Its diagnosis is more likely in advanced ages, with the older population being the most seen in consultations. Poly(ADP-ribose) inhibitors (PARPi) have changed OC clinical practice and evolution, showing great benefit. However, there is a lack of evidence of PARPi in elderly population that can impact the therapeutic decision and the safety/efficacy. It is necessary to avoid age as limiting factor in PARPis prescription. We conducted a review of the most relevant randomized phase III trials of maintenance PARPi after first-line treatment of advanced OC. We observed the lack of a single criterion for considering older patients, varying among trials. There is a benefit of PARPis in different populations. However, PARPi effect on quality of life is not reported, something of great relevance considering their vulnerability. Measures are needed to benefit older patients to better adapt PARPi treatment.

The value of combined MRI, enhanced CT and 18F-FDG PET/CT in the diagnosis of recurrence and metastasis after surgery for ovarian cancer

The purpose of this article was to investigate the value of combined MRI, enhanced CT and Ninety-five ovarian cancer patients were selected as the study subjects, all of them underwent surgical treatment, and MRI, enhanced CT and The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of the combined group were higher than those of MRI and enhanced CT for recurrence and metastasis of ovarian cancer after surgery, and the specificity, accuracy and positive predictive value of the combined group were higher than those of the The combination of MRI, enhanced CT and

Fertility preservation in hematological cancer patients

A signature of circulating miRNAs predicts the prognosis and therapeutic outcome of taxane/platinum regimen in advanced ovarian carcinoma patients

Ovarian carcinoma (OC) is ranked as the eighth most lethal gynecological cancer due to late diagnosis and high recurrence. Existing biomarkers are lacking to predict the recurrence and stratify patients who are likely to benefit from chemotherapy. MicroRNAs (miRNAs/miRs) are persistently present in humans and are capable of predicting treatment outcomes. Thus, the purpose of the study was to assess the potential of circulatory miRNAs to predict the efficacy of OC. Newly diagnosed n = 208 OC patients were administrated neoadjuvant/adjuvant chemotherapy (taxane + platinum) after surgery. Their demographic, gynecologic, clinical parameters, response, and survival were recorded. MiR-27a, miR-182, miR-199a, miR-214, and miR-591 were taken and the expression were analyzed using real-time PCR at different treatment intervals. Further, its prognostic value (Kaplan-Meier, and Cox regression analysis) and diagnostic importance (receiver operating characteristic curve) were validated. The mean age of patients with poorly differentiated (45.2%) serous OC was 48.69 ± 10.38. The majority experienced menarche at ≥ 12 (62.2%) with poor menstrual hygiene (81.8%) and were post-menopausal (69.4%), some were associated with high risk of survival (HR =  > 1). MiRNA signature showed three over-expression and two under-expression (miR-27a, miR-182, and miR-214; miR-199a and miR-591) in advanced OC compared to the control (P=   1). ROC analysis showed enhanced the diagnostics accuracy (< 0.001). Our findings indicate that circulating miRNAs might be a potential minimally invasive diagnostic marker for treatment outcome and recurrence in ovarian carcinoma.

Current status of fertility preservation in a Spanish tertiary public hospital: multidisciplinary approach and experience in over 1500 patients

Molecular profile in endometrial carcinoma: can we predict the lymph node status? A systematic review and meta-analysis

Molecular classification of endometrial cancer (EC) has become a promising information to tailor preoperatively the surgical treatment. We aimed to evaluate the rate of lymph node metastases (LNM) in patients with EC according to molecular profile. A systematic review and meta-analysis were performed according to PRISMA guidelines by searching in two major electronic databases (PubMed and Scopus), including original articles reporting lymph node metastases according to the molecular classification of EC as categorized in the ESGO-ESMO-ESP guidelines. Fifteen studies enrolling 3056 patients were included. Pooled prevalence LNM when considering only patients undergoing lymph node assessment was 4% for POLE-mutated (95%CI: 0-12%), 22% for no specific molecular profile (95% CI: 9-39%), 23% for Mismatch repair-deficiency (95%CI: 10-40%) and 31% for p53-abnormal (95%CI: 24-39%). The presence of LNM seems to be influenced by molecular classification. P53-abnormal group presents the highest rate of nodal involvement, and POLE-mutated the lowest.

Management of ocular toxicity in patients with gynecologic cancer receiving novel antibody–drug conjugates: a narrative review

Antibody-drug conjugates (ADCs) represent a promising therapeutic approach in gynecologic cancers, particularly ovarian and cervical malignancies. Agents such as mirvetuximab soravtansine, and tisotumab vedotin, targeting folate receptor alpha and tissue factor, respectively, reported clinical efficacy in patients with limited options. However, their use is associated with ocular toxicities, including keratopathy, blurred vision, and dry eye, which may impact adherence and quality of life. This review summarizes current evidence on the incidence, pathophysiology, and clinical presentation of ADC-related ocular adverse events in gynecologic oncology. It also provides practical, evidence-based strategies for the prevention, monitoring, and management of these adverse events. Interventions include prophylactic topical therapies, supportive care measures, treatment delays or dose modifications, and herpes zoster vaccination. Comprehensive management of ocular toxicities is essential to ensure the safe and sustained use of ADCs, preserving both therapeutic benefit and patient well-being. Further research is warranted to optimize preventive and management protocols.

Applications of single-cell transcriptomics: updated insights in endometrial cancer

Endometrial cancer (EC) presents a major global health challenge due to its heterogeneity and complex pathophysiology. The tumor microenvironment (TME), comprising stromal cells, immune cells, endothelial cells, and non-cellular components, critically influences EC progression. Single-cell RNA sequencing (scRNA-seq) has revolutionized our understanding of EC by revealing TME cellular heterogeneity and interactions. This review synthesizes recent scRNA-seq applications in EC, focusing on two key areas: ① Mapping transcriptional heterogeneity across major cellular components (epithelial, stromal, endothelial, and immune cells); ② Elucidating the factors driving tumor evolution, immune evasion, and differential immunotherapy response. Collectively, these scRNA-seq-derived insights into the dynamic TME ecosystem provide the foundation for translating basic discoveries toward clinical applications. Such advances could thereby promote TME-based personalized therapies and more accurate prognostic predictions.

The role of toll-like receptors (TLRs) and their therapeutic applications in endometrial cancer

Endometrial cancer (EC) is developed nations' most prevalent form of gynecologic cancer. Patients are frequently diagnosed with EC when the tumor is still limited to the uterus. Patients without tumor metastasis have a 5-year survival rate ranging from 80 to 90%; however, almost 16.8% of EC patients develop a metastatic form of the tumor. In the early stages of tumorigenesis, the immune system is able to identify aberrant cells as non-self, therefore providing the optimal pro-inflammatory microenvironment for the elimination of cancer cells. Although, chronic inflammation can be a crucial aspect of tumor development. Toll-like receptors (TLRs), as the main pattern recognition receptors (PRRs) in innate immunity, may stimulate an inflammatory response and provide cell survival in the tumor microenvironment (TME). TLRs are vital immunomodulators that may significantly impact the development of gynecologic malignancies. Therefore, TLR inhibitors are being researched for their possible benefits in treating gynecologic cancers. The aim of this study is to review the current knowledge in this field and provide some insight into the therapeutic potential of TLR inhibitors in EC.

Comparing the survival rates of patients with stage IIIC endometrial cancer undergoing sandwich therapy to those undergoing sequential chemotherapy and radiotherapy: a meta-analysis

The use of additional treatment after surgery for stage IIIC endometrial cancer (EC) according to the Federation of Gynecology and Obstetrics (FIGO) is still a topic of discussion. This meta-analysis examined the effects of sandwich treatment and sequential treatment on the survival of individuals diagnosed with stage IIIC EC. We examined the literature from various databases regarding the overall survival (OS) and adverse effects of the two additional therapies following surgery in individuals diagnosed with stage IIIC EC. Revman 5.4.1 was utilized to combine hazard ratios (HR) and their corresponding 95% confidence intervals (95% CI) for OS and toxicities. The findings comprised of five retrospective investigations involving a combined total of 800 individuals. The patients who underwent sandwich treatment did not demonstrate a notable improvement in survival rates over a period of 3 years. Upon eliminating the impact of extensive samples, it was discovered that sandwich therapy exhibited a superior 5-year overall survival compared to patients receiving sequential therapy. The effectiveness of sandwich therapy was superior to sequential therapy in terms of a 3-year OS for non-endometrioid histology, although the outcome did not reach statistical significance. The toxicities of both treatments were similar. In terms of long-term survival, sandwich therapy was found to be more advantageous than sequential therapy for patients with stage IIIC EC, with no significant disparity observed in the 3-year OS and toxicities between the two treatments. Sandwich therapy exhibited a tendency towards improved effectiveness in patients with histology other than endometrioid.

Single-cell transcriptome analysis identifies subclusters and signature with N-glycosylation in endometrial cancer

Endometrial cancer (EC) is a prevalent gynecologic cancer, with worldwide increasing incidence and disease-associated mortality. N-glycosylation, a critical post-translational modification, has been implicated in cancer progression and immune response modulation. We aimed to elucidate the role of N-glycosylation-related genes on EC cell heterogeneity, prognosis, and immunotherapy response. Data from single-cell RNA sequencing (scRNA) of five patients with EC were acquired from the Gene Expression Omnibus (GEO) database. Nonnegative matrix factorization (NMF) was used to identify cell subtypes related to N-glycosylation from a scRNA matrix. Subsequently, a consensus prognostic signature by integrating 101 combinations of 10 machine learning algorithms. The response to immunotherapy in EC was further examined by multiple algorithms. Our findings identified 11,020 differentially expressed genes (DEGs), of which 34 N-glycosylation-related DEGs were remarkably associated with overall survival (OS) in EC. Single-cell RNA sequencing analysis revealed 30,233 cells divided into eight clusters, with T cells and epithelial cells showing distinct functional characteristics. NMF clustering further classified malignant cells into four subtypes: N-glycosylation-C0, Glycosphingolipid-C1, O-GalNAc-C2, and Elongation-C3. The O-GalNAc-C2 subtype exhibited the highest metabolic pathway activity and activation of transcription factors SOX4, JUND, and FOS. Additionally, cell-cell interaction networks highlighted the MK signaling pathway as a critical mediator of intercellular communication. An integrated machine learning framework generated a prognostic model comprising eight DEGs (LAMC2, KRT7, IL32, KRT18, SERPINA1, PGR, AKAP12, EDN2), achieving an average C-index of 0.712 in training and validation cohorts. A low-risk score implies more significant immune cell infiltration and better response to immunotherapy. Our study underscores the role of N-glycosylation-related genes in EC prognosis and immunotherapy response prediction, and may provide a basis for the development of targeted therapies and personalized treatment strategies.

Construction of prediction model for prognosis of uterine corpus endometrial carcinoma based on pyroptosis gene

To assess the expression of genes that are relevant to pyroptosis and the relationship between these genes and prognosis in uterine corpus endometrial carcinoma (UCEC). The research identifies 16 pyroptosis regulators with different expressions in normal endometrium and UCEC. In accordance with the differentially expressed genes (DEGs), the various kinds of UCEC are classified into two sub-types. With the help of the Cancer Genome Atlas (TCGA), the prognostic value of all pyroptosis-related genes for survival was assessed, and a multigene model has constructed accordingly. Ten genes were modeled by applying the minimum criteria for determining risk score selection (LASSO) Cox regression method. Meanwhile, by referring to the TCGA atlas, UCEC patients were divided into the high- and low-risk subgroups. The effects of the gene with significant differences on the proliferation of two cancer cells were also verified. The survival rate of UCEC cases with higher risk was higher than that with lower risk (P < 0.001). Through the median risk score of TCGA atlas, UCEC cases were ranked as patients with higher risk and patients with lower risk. The low risk has a significant relationship with the prolongation of overall survival (OS) (p = 0.001) in the low-risk subgroup. Moreover, the KEGG and gene ontology (GO) enrichment models indicated that among the patients in the high-risk subgroup, their immune-related genes were concentrated but with decreased immune status. The apoptosis-related genes are crucial for the immunity of tumors and may forecast the prognosis of UCEC.

STAT3 inhibitor BBI608 reduces patient-specific primary cell viability of cervical and endometrial cancer at a clinical-relevant concentration

Aberrant activation of STAT3 signal pathway promotes tumor progression in many solid tumor types, including cervical cancer and endometrial cancer. BBI608, the STAT3 inhibitor had been reported in previous studies for restraining cancer stem cells. However, whether BBI608 is available for inhibiting the proliferation of cervical cancer or endometrial cancer remains poorly understood. This study investigated the anti-tumor effect and molecular mechanism of BBI608 on the patient-specific primary cells (PSPC) generated from cervical and endometrial cancer in vitro. PSPCs were obtained from four patients via biopsy. The cell viability was analyzed by the CCK8 assay. The PSPCs were treated with various concentrations of BBI608 or/and paclitaxel; and then, western blot was applied to investigate the expression of phosphorylated STAT3 (pSTAT3). The PSPCs cell viability was reduced after treated with BBI608 at a lower concentration. Western blot results showed a reduction trend of pSTAT3 after PSPCs treated with BBI608. Our results demonstrated that BBI608 at the certain concentrations worked well in reducing the cell viability of PSPC from the patients who suffered from cervical cancer and endometrial cancer. In this study, the patient-specific primary cell (PSPC) was used as the pre-clinical model for investigating the efficiency of BBI608 in reducing cancer cells viability. BBI608, at a clinical-relevant concentration, had valid efficiency in PSPCs from the patients. The dose of drugs treatment and the measured results were more valuable for further guiding clinical trials.

Downregulation of HOXA11 enhances endometrial cancer malignancy and cisplatin resistance via activating PTEN/AKT signaling pathway

Endometrial cancer is the most common malignant tumor of female genital system worldwide. Homeobox A11 (HOXA11) is an evolutionarily conserved Homeobox gene closely implicated in carcinogenesis. However, the mechanisms of HOXA11 in the progression and cisplatin resistance of endometrial cancer remain unclear. The expression of HOXA11 was analyzed based on 548 endometrial cancer and 35 control tissues from The Cancer Genome Atlas (TCGA) database. Transwell assay was performed to investigate the effect of HOXA11 on endometrial cell migration and invasion. TUNEL staining was carried out to assay the role of HOXA11 in endometrial cell apoptosis. Western blot was employed to detect the protein levels of B cell lymphoma-2 (Bcl-2), Bcl-2 associated X (Bax), cleaved caspase-3, matrix metalloproteinase-2/9 (MMP/9), phosphatase and tensin homolog (PTEN), protein kinase B (AKT) and p-AKT. TCGA data showed that HOXA11 expression was significantly down-regulated in endometrial cancer tissue samples. The overexpression of HOXA11 promoted the apoptosis, but inhibited the proliferation, migration and invasion of endometrial cancer cells. HOXA11 knockdown with small interfering RNA (siRNA) considerably repressed cell apoptosis, while promoted cell proliferation, migration, and invasion through PTEN/AKT signaling pathway. Interestingly, HOXA11 was lowly expressed in Ishikawa cells treated with cisplatin. In addition, HOXA11 knockdown increased the resistance of endometrial cancer to cisplatin through activating PTEN/AKT signaling pathway. Low HOXA11 expression may promote the proliferation, migration, invasion of endometrial cancer cells, and increase their resistance to cisplatin through activating PTEN/AKT pathway.

Expression of bone morphogenetic protein 10 in cases with endometrial carcinoma and its clinical significance

To investigate the expression of bone morphogenetic protein 10 (BMP-10) in patients with endometrial carcinoma (EC) and its clinical significance. Totally 143 cancer tissue specimens were sampled from patients with EC and retrospectively analyzed. The immunohistochemical method was adopted for quantifying BMP-10 in EC tissues. Then the patients were assigned to high and low BMP-10 expression groups. The Kaplan-Meier method and log-rank test were adopted to compare the difference of tumor-free survival (TFS) rate and overall survival (OS) rate between the two groups. The COX proportional hazard model was used to analyze independent risk factors affecting the TFS rate and OS rate of patients with EC. There were 80 patients (55.94%) with low BMP-10 expression and 63 patients with high BMP-10 expression (54.06%). BMP-10 expression was significantly correlated with International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.001), myometrial invasion depth (P < 0.001), histological grade (P < 0.001), and lymph node metastasis (P = 0.009). Additionally, TFS rate (P = 0.004) and OS rate (P = 0.003) in the low BMP-10 expression group were notably lower than those in the high BMP-10 expression group. Multivariate analysis showed that BMP-10 expression (HR: 13.712, 95% CI 1.823-103.158, P = 0.011) was an independent risk factor for the TFS of patients with EC. FIGO stage (P = 0.001) and BMP-10 expression (HR: 8.655, 95% CI 1.098-68.215, P = 0.020) were independent risk factors for the OS of such patients. BMP-10 can be adopted as a molecular marker for predicting the poor prognosis of patients with EC.

Survival outcomes and prognostic factors of endometrial stromal sarcoma and undifferentiated uterine sarcoma

To review the diagnostic and therapeutic procedures of patients diagnosed with Endometrial Stromal Sarcoma (ESS) and Undifferentiated Uterine Sarcoma (USS) at our institution and investigate their clinical outcomes and factors affecting prognosis. We retrospectively collected demographic data, preoperative diagnostic methods and therapeutic management of patients treated for ESS and UUS between January 1995 and December 2019 at Vall d'Hebron Barcelona Hospital Campus, Spain. Overall survival and disease-free survival were calculated. Cox proportional-hazards regression models were calculated. Sixty-three patients were included in the study, of which 51(81%) had a diagnosis of ESS and 12(19%) of UUS. Twenty patients (31.7%) were diagnosed after a previous non-oncologic surgery, and 12 of them (60%) suffered from tumor disruption. Cytoreductive procedures were needed in 29 patients (46%), and optimal cytoreduction was achieved in 80.9% of the patients. The median follow-up was 7.6 years (IQR = 0.99-14.31). Five-year overall survival was 57.6% (44.2-68.8) and was significantly better for low-grade ESS (LG-ESS) patients (p < 0.01). Five-year disease-free survival was 57.1% (42.8-69.1) and was also significantly higher in LG-ESS cohort (p = 0.03). After multivariate analysis histological type, age, FIGO stage, optimal surgery and mitotic index were found significantly correlated with survival. For high-grade EES (HG-ESS) and USS patients adjuvant radiotherapy also correlated with improved survival. Overall survival and disease-free survival are significantly better in patients with LG-ESS cohort. HG-ESS and UUS show similar survival outcomes. Age, FIGO stage, optimal surgery and histological type were significantly correlated with survival in the global cohort, whilst adjuvant radiotherapy correlated with improved survival in HG-ESS and UUS patients.

Radiation-induced lymphopenia: the main aspects to consider in immunotherapy trials for endometrial and cervical cancer patients

Although the chemotherapy-induced depletion of circulating white blood cells (WBC) is well recognized, the impact of exclusive radiotherapy (RT) on the different subpopulations of WBC remains unexplored. This may be important for immunotherapy administrated in combination with radiation, especially in malignant tumors usually treated with RT or chemoradiotherapy (CRT), and characterized by a high mutational burden, such as endometrial (EC) or cervical cancer (CC). We aimed to evaluate the impact of RT and CRT on circulating WBC in uterine cancers and its correlation with survival. A total of 202 consecutive patients with uterine cancers treated with RT or CRT between 2009 and 2016 in a large European center and with available basal and post-treatment blood tests were retrospectively evaluated. EC and CC patients were analyzed separately. The differences between pre- and post- treatment WBC mean values were evaluated independently in patients treated with CRT and exclusive RT. Two-sided T test for paired samples and Kaplan-Meier curves were applied for analysis (p value < 0.05, SPSS v.23). Among EC patients, 29 received CRT and 34 exclusive postoperative RT, while in CC cohort, 105 were treated with CRT and 34 with RT. In both cohorts, CRT affected significantly all WBC subtypes, whereas exclusive RT decreased only lymphocytes population (p = 0.000). Radiation-induced lymphopenia (RIL) had no impact on survival outcomes. The selective depletion of lymphocytes after RT was significant in both EC and CC. Our results are of interest for further research on RIL and for design of immunotherapy-based clinical trials.

Oncologic impact of micrometastases or isolated tumor cells in sentinel lymph nodes of patients with endometrial cancer: a meta-analysis

There is a gap in knowledge regarding the impact of micrometastases (MIC) and isolated tumor cells (ITCs) found in the sentinel lymph nodes of patients with endometrial cancer. Here, we present a meta-analysis of the published literature on the rate of MIC and ITCs after lymphatic mapping and determine trends in postoperative management. Literature search of Medline and PubMed was done using the terms: micrometastases, isolated tumor cells, endometrial cancer, and sentinel lymph node. Inclusion criteria were: English-language manuscripts, retrospectives, or prospective studies published between January 1999 and June 2019. We removed manuscripts on sentinel node mapping that did not specify information on micrometastases or isolated tumor cells, non-English-language articles, no data about oncologic outcomes, and articles limited to ten cases or less. A total of 45 manuscripts were reviewed, and 8 studies met inclusion criteria. We found that the total number of patients with MIC/ITCs was 286 (187 and 99, respectively). The 72% of patients detected with MIC/ITCs in sentinel nodes received adjuvant therapies. The MIC/ITCs group has a higher relative risk of recurrence of 1.34 (1.07, 1.67) than the negative group, even if the adjuvant therapy was given. We noted that there is an increased relative risk of recurrence in patients with low-volume metastases, even after receiving adjuvant therapy. Whether adjuvant therapy is indicated remains a topic of debate because there are other uterine factors implicated in the prognosis. Multi-institutional tumor registries may help shed light on this important question.

CircRNA-regulated glucose metabolism in ovarian cancer: an emerging landscape for therapeutic intervention

Ovarian cancer (OC) has the highest mortality rate among female reproductive system tumours, with limited efficacy of traditional treatments and 5-year survival rates that rarely exceed 40%. Circular RNA (circRNA) is a stable endogenous circular RNA that typically regulates protein expression by binding to downstream miRNA. It has been demonstrated that circRNAs play an important role in the proliferation, migration, and glucose metabolism (such as the Warburg effect) of OC and can regulate the expression of glucose metabolism-related proteins such as GLUT1 and HK2, promoting anaerobic glycolysis of cancer cells, increasing glucose uptake and ATP production, and affecting energy supply and biosynthetic substances to support tumour growth and invasion. This review summarises the formation and characteristics of circRNAs and focuses on their role in regulating glucose metabolism in OC cells and their potential therapeutic value, providing insights for identifying new therapeutic targets.

The serum LDH level and KELIM scores are potential predictors of a benefit from bevacizumab first-line therapy for patients with advanced ovarian cancer

The survival benefit of first-line treatment with bevacizumab in advanced ovarian cancer patients are multifaceted. In our study, we aimed to identify potential markers of bevacizumab efficacy to help predict which patients would experience survival benefits. This was a retrospective analysis of 114 patients examined from January 1, 2015, to March 1, 2023, and data on clinical, biological, and imaging variables, such as ascites, serum LDH, and CA125, were extracted from electronic medical records. We performed a correlation analysis and principal component analysis to investigate correlations among variables and reduce their dimensionality. Then, univariate and multivariate Cox proportional hazards regression analyses were used to identify the predictors of progression-free survival. Favorable KELIM score (≥ 1, HR 0.376, 95% CI [0.202-0.700], p = 0.002), which indicated better chemosensitivity, and lower LDH levels (≤ 210 U/L, HR 38.73, 95% CI [6.108-245.6], p < 0.001) were found to be independent predictors of a treatment benefit with bevacizumab in patients with advanced ovarian cancer. Regardless of LDH level, patients with favorable KELIM scores had a higher progression-free survival (PFS) benefit (p = 0.18). Among patients with unfavorable KELIM scores, those with higher LDH levels had the lowest PFS benefit (median: 11.5 months, p = 0.0059). Patients with poor chemosensitivity and low LDH levels are more likely to benefit from first-line bevacizumab treatment. The combination of the two markers can be a helpful predictor of patients who are most likely to benefit from treatment and a guide for treatment decisions-making. Retrospectively registered: 2020-MD-371, 2020.10.12.

HPV-driven cancer: from epidemiology to the HPV-driven tumor board proposal, everything you wanted to know but were afraid to ask

Human papilloma virus (HPV)-related cancers are well-known clinical entities in different body sites. Cervix, anus, and oropharynx are the most common tumors related to the virus infection. The aim of this work was to highlight similarities and differences among HPV-related cancers of different subsites. The narrative review was focused on the following topics: (1) epidemiology, (2) prognostic factors, (3) treatment approaches, (4) radiomic analysis, (5) radiosensitivity, (6) de-escalation strategies. Common aspects as well as differences have been highlighted for cervical, anal and oropharyngeal HPV-related tumors. Common prognosticators in terms of patients characteristics (anemia, smoking habits), tumor histology (lymph node extracapsular extension) biological features (high circuating HPV DNA), blood cell immunomodulating response (high level of tumor-infiltrating lymphocytes and high neutrophil-to-lymphocyte ratio) as good parameters of radiosensitivity (radiosensitivity index RSI, and genomic adjusted radiation dose GARD) have been found among the analyzed tumor subsites. On the contrary, other aspects like treatment approaches (different RT techniques and doses), radiomic analysis and de-intensification strategies were found to be different among tumors. HPV-related tumors have several common prognostic and predictive features that do not translate into common therapeutic approaches and de-intensification strategies. A better understanding of which factors are associated with a high risk of early recurrence or favourble clinical outcomes could help in guiding clinical assessment and screening activities and might improve efforts for precision medicine.

Vaginal micro-environment disorder promotes malignant prognosis of low-grade cervical intraepithelial neoplasia: a prospective community cohort study in Shanxi Province, China

Emerging evidence suggests that vaginal micro-environment disorder is closely related to the development of cervical lesions. Low-grade cervical intraepithelial neoplasia (CIN1), as an early stage of cervical lesions, exhibits a high risk of progressing to high-grade lesions or even cervical cancer. However, the effect of vaginal micro-environment on the malignant prognosis of CIN1 remains uncertain. A total of 504 patients diagnosed with CIN1 by pathology, who were from the population-based cohorts established in Shanxi Province, China, were enrolled and followed up for 2 years. Micro-environmental factors such as vaginal pH, cleanliness, hydrogen peroxide (H Abnormal vaginal pH (HR = 1.472, 95%CI 1.071-2.022), cleanliness (HR = 1.446, 95%CI 1.067-1.960), H Vaginal micro-environment disorder could promote CIN1 malignant prognosis, particularly in HR-HPV-infected women. Taking micro-environmental factors as the breakthrough, our study provides a feasible vision for preventing early stage cervical lesions.

Inhibiting SNX10 induces autophagy to suppress invasion and EMT and inhibits the PI3K/AKT pathway in cervical cancer

Cervical cancer (CC) is a prevalent malignancy among women with high morbidity and poor prognosis. Sorting nexin 10 (SNX10) is a newly recognized cancer regulatory factor, while its action on CC progression remains elusive. Hence, this study studied the effect of SNX10 on CC development and investigated the mechanism. The SNX10 level in CC and the overall survival of CC cases with different SNX10 expressions were determined by bioinformatics analysis in GEPIA. The SNX10 expression in tumor tissues and clinical significance were studied in 64 CC cases. The overall survival was assessed using Kaplan-Meier analysis. The formation of LC3 was evaluated using immunofluorescence. Cell invasion was measured using the Transwell assay. Epithelial-to-mesenchymal transition (EMT) was determined by observing cell morphology and assessing EMT marker levels. A xenograft tumor was constructed to evaluate tumor growth. SNX10 was elevated in CC tissues and cells, and the CC cases with high SNX10 levels exhibited poor overall survival. Besides, SNX10 correlated with the FIGO stage, lymph node invasion, and stromal invasion of CC. SNX10 silencing induced CC cell autophagy and suppressed CC cell invasion and EMT. Meanwhile, silenced SNX10 could suppress invasion and EMT via inducing autophagy. Furthermore, SNX10 inhibition suppressed the PI3K/AKT pathway. Moreover, silenced SNX10 restrained the tumor growth, autophagy, and EMT of CC in vivo. SNX10 was enhanced in CC and correlated with poor prognosis. Silenced SNX10 induced autophagy to suppress invasion and EMT and inhibited the PI3K/AKT pathway in CC, making SNX10 a valuable molecule for CC therapy.

Early salvage therapy with anti-PD-1 antibody Camrelizumab in patients with advanced cervical cancer: a retrospective study

To observe the clinical efficacy of Camrelizumab in patients with advanced cervical cancer who presented with resistance to initial therapy. We retrieved data from 25 patients with advanced (stage IIA2-IV) cervical cancer who were administered a combination salvage therapy with Camrelizumab due to the poor response to initial chemotherapy. The primary outcome was objective response rate (ORR) and disease control rate (DCR), the secondary endpoints included progression-free survival (PFS) and the occurrence of adverse events. To evaluate its long-term effect on PFS, we included 64 patients diagnosed with stage IIA2-IV during the study period, who were responsive to initial radiotherapy or chemotherapy and received conventional therapy as control. Camrelizumab exhibits a high salvage treatment efficacy, with ORR of 80.0% (20/25) and DCR of 88.0% (22/25) in Camrelizumab salvage group (CS group). The PFS in CS group was significantly longer than that in control group. The median follow-up time were 18.1 and 18.3 months in the CS group and the control group, respectively, and neither achieved median PFS. The adverse event (AEs) rates in the CS and control groups were 52.0% (13/25) and 51.6% (33/64), in which the most common adverse events were myelosuppression, cutaneous capillary endothelial proliferation (CCEP), and elevated liver enzymes, and the grade of AEs was less than grade 3 in all patients. Camrelizumab demonstrated promising efficacy and safety as the early salvage treatment for patients with advanced cervical cancer.

Association of albumin, neutrophil–lymphocyte ratio and lymphocytes with clinical stage in cervical cancer patients

To determinate the association between of albumin, neutrophil-lymphocyte ratio and lymphocytes (NLR) with clinical stage in cervical cancers. Design a retrospective cross-sectional study of consecutive subjects diagnosed with cervical cancer for the first time. The Bethesda system was used for histological diagnosis and the subjects were stratified with the FIGO system, considering stages IA to IIB as localized; while, IIIA and IVB as advanced stages. Albumin, NLR and lymphocytes were evaluated as inflammatory biomarkers and the cut-off points generated by the ROC curves were albumin < 3 mg/dL, NLR ≥ 2.0 and lymphocytes < 1.2 10 A total of 152 patients were analyzed, with mean age of 49.3 ± 14.0 years. Epidermoid cancer was the most frequent in 70.6% and 51.3% were classified as advanced clinical stages. A bivariate analysis showed significant relationships between advanced clinical stages and albumin < 3 mg/dL with OR 5.72 (CI95% 2.62-12.4; p < 0.001); for NLR ≥ 2.0 an OR 2.53 (CI95% 1.34-4.89; p = 0.005) and for lymphocytes < 1.2 10 Albumin levels < 3 mg/dL, NLR ≥ 2.0 and lymphocytes < 1.2 10

SEOM-GEICO clinical guidelines on endometrial cancer (2025)

Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. Although most cases are diagnosed at an early stage, prognosis in case of relapse or metastasis remains poor. Molecular characterization of EC is highly recommended as it allows more accurate risk stratification and may modify treatment recommendations. The updated FIGO 2023 staging of EC highlights the importance of traditional clinicopathological factors, while underlining the need for molecular classification to predict outcomes. In early-stage EC, standard treatment consists of total hysterectomy and bilateral salpingo-oophorectomy. Lymph node evaluation remains controversial, as the benefits of systematic lymphadenectomy are unclear. Adjuvant treatment, consisting of radiotherapy, brachytherapy, and chemotherapy, should be chosen according to risk category. In women with advanced or recurrent EC, the combination of carboplatin and paclitaxel has long been standard treatment. However, therapeutic options have changed recently due to advances in immunotherapy. The aim of this guideline is to summarize the current evidence for the diagnosis, treatment, and follow-up of EC, and to provide evidence-based recommendations for clinical practice.

PARP inhibitors-associated thrombosis in patients with ovarian cancer: a study of the Spanish Society of Medical Oncology (SEOM) thrombosis and cancer group

To determine the real-world incidence and predictive factors for venous and arterial thromboembolic events (VTE/AT) in ovarian cancer patients treated with poly-(ADP-ribose) polymerase inhibitors (iPARP). A multicenter retrospective study involving 329 ovarian cancer patients who initiated iPARP treatment between January 2015 and December 2022. The primary outcome was the incidence of VTE/AT. Secondary outcomes included predictive factors for thrombosis and the impact of thrombosis on overall survival (OS). Data were analyzed using logistic regression and Kaplan-Meier survival analysis. The incidence of VTE/AT was 4.9% (16/329). BRCA2 mutations were significantly more prevalent among patients who developed VTE/AT (56.3% vs. 19.2%; p < 0.001). Combined treatment with bevacizumab was significantly associated with a decreased risk of thrombosis (OR: 0.262; 95% CI: 0.095-0.724; p = 0.010). No statistically significant differences were observed in the median OS between patients who experienced VTE/ATE (63 months) and those who did not (47 months), with a p value of 0.876. BRCA2 mutations could be a significant predictor for VTE/AT among ovarian cancer patients treated with iPARP. Concomitant treatment with bevacizumab may offer protection against thrombotic events, although a concomitant bias cannot be ruled out. These findings may be of interest when designing future clinical trials in the field of thromboprophylaxis.

SEOM clinical guidelines in hereditary breast and ovarian cancer (2019)

AbstractMutations inBRCA1andBRCA2high penetrance genes account for most hereditary breast and ovarian cancer, although other new high-moderate penetrance genes included in multigene panels have increased the genetic diagnosis of hereditary breast and ovarian cancer families by 50%. Multigene cancer panels provide new challenges related to increased frequency of variants of uncertain significance, new gene-specific cancer risk assessments, and clinical recommendations for carriers of mutations of new genes. Although clinical criteria for genetic testing continue to be largely based on personal and family history with around a 10% detection rate, broader criteria are being applied with a lower threshold for detecting mutations when there are therapeutic implications for patients with breast or ovarian cancer. In this regard, new models of genetic counselling and testing are being implemented following the registration of PARP inhibitors for individuals who display BRCA mutations. Massive sequencing techniques in tumor tissue is also driving a paradigm shift in genetic testing and potential identification of germline mutations. In this paper, we review the current clinical criteria for genetic testing, as well as surveillance recommendations in healthy carriers, risk reduction surgical options, and new treatment strategies in breast cancer gene-mutated carriers.

SEOM clinical guidelines for cervical cancer (2019)

AbstractCervical cancer (CC) is the fourth most common cancer in women worldwide, strongly linked to high-risk human papilloma virus infection. In high-income countries, the screening programs have dramatically decreased the incidence of CC; however, the lack of accessibility to them in developing countries makes CC an important cause of mortality. Clinical stage is the most relevant prognostic factor in CC. The new FIGO staging system published in 2018 is more accurate than the previous one since it takes into account the lymph node status. In early stages, the primary treatment is surgery—with some concerns recently raised regarding minimally invasive surgery because it might decrease survival—or radiotherapy, whereas concomitant chemo-radiotherapy is the conventional approach in locally advanced stages. For recurrent or metastatic CC, the combination of chemotherapy plus bevacizumab is the preferred therapy. Immunotherapy approach based on checkpoint inhibitors is evolving as the election therapy following failure to platinum therapy.

Clinicopathologic and prognostic significance of tumor-associated macrophages in cervical cancer: a systematic review and meta-analysis

Abstract Objectives The role of tumor-associated macrophages (TAMs) in cervical cancer (CC) remains controversial. Here, we report a meta-analysis of the association between TAMs infiltration and clinical outcomes. Methods PubMed, Embase, Web of Science, and CNKI were searched systematically from inception until December 20, 2023. Studies involving TAMs and prognosis, clinical, or pathological features were included. Quality assessments of the selected studies were assessed. The fixed-effect or random-effects model, standard mean difference (SMD), odds ratios (OR), or hazard ratios (HR) with 95% confidence intervals (CIs) were used as the effect size estimate. Results 26 eligible studies with 2,295 patients were identified. Our meta-analysis revealed that TAMs were overexpressed in CC (OR = 12.93, 95% CI = 7.73–21.61 and SMD = 1.58, 95% CI = 0.95–2.21) and that elevated TAM levels were strongly associated with lymph node metastasis (LNM) (SMD = 0.51, 95% CI = 0.90–2.01) and FIGO stages (SMD = 0.46, 95% CI = 0.08–0.85). Subgroup analysis indicated a significant positive correlation between LNM and TAMs density in tumor stroma, but not in cancer nests (SMD = 0.58, 95% CI = 0.31–0.58). Furthermore, in early stage, a stronger correlation exists between LNM and TAM density (SMD = 1.21, 95% CI = 0.75–1.66). In addition, it revealed that patients with high TAMs expression had poorer overall survival (OS) (HR = 2.55 95% CI = 1.59–4.07) and recurrence-free survival (RFS) (HR = 2.17, 95% CI = 1.40–3.35). Conclusions Our analyses suggest that a high density of TAMs predicts adverse outcomes in CC.

Prognostic value of systemic inflammation response indexes obtained from the complete blood count in patients treated for advanced ovarian carcinoma in front line

Abstract Objective Various systemic inflammation response indexes (SIRI) have repeatedly been described as prognostic factors in ovarian cancer. They have not been validated in prospective trials and published results are sometimes contradictory. We aimed to explore their role in a cohort of patients diagnosed with stage III and IV ovarian cancer treated at our institution. Methods We retrospectively examined the prognostic influence of the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the monocyte-to-lymphocyte ratio (MLR), the red cell distribution width (RDW), and the mean platelet volume (MPV). Results A total of 77 patients were analyzed. NLR &gt; 2.243 at diagnosis, NLR before primary surgery, MLR at diagnosis, PLR &gt; 289.1 at diagnosis, and PLR at diagnosis were significant in univariate Cox regression for progression-free survival, but none of them retained their significance in the multivariate Cox regression analysis. For overall survival, NLR &gt;  = 2.53 at diagnosis, MLR &gt;  = 0.245 at diagnosis, and PLR &gt;  = 198.3 at diagnosis resulted significant in univariate COX regression; only PLR &gt;  = 198.3 at diagnosis retained its significance in the multivariate analysis. Conclusion In our cohort, PLR &gt;  = 198.3 was an independent prognostic factor for worse OS. The definitive role of SIRI in ovarian cancer has not yet been established. If their value as prognostic factors could finally be established, they would become a simple and economical method to predict prognosis in patients with advanced ovarian cancer. Therefore, it is time to conduct prospective, multicenter studies with larger samples to definitively establish its role in ovarian cancer, if any.

LINC01119 encapsulated by cancer-associated adipocytes-derived exosomes promotes M2 polarization of macrophages to induce immune escape in ovarian cancer in a 3D co-culture cell-based model

In the present study, we sought to clarify the role of LINC01119 delivered by cancer-associated adipocytes (CAAs)-derived exosomes (CAA-Exo) and its mechanistic actions in ovarian cancer (OC). The expression of LINC01119 was determined in OC, and the relationship between LINC01119 expression and the prognosis of OC patients was analyzed. Besides, 3D co-culture cell models were constructed using green fluorescent protein-labeled OC cells and red fluorescent protein-labeled mature adipocytes. Mature adipocytes were co-cultured with OC cells to induce CAA. Macrophages treated with CAA-Exo were co-cultured with SKOV3 cells following ectopic expression and depletion experiments of LINC01119 and SOCS5 to detect M2 polarization of macrophages, PD-L1 level, proliferation of CD3 LINC01119 was elevated in the plasma Exo of OC patients, which was related to shorter overall survival in OC patients. LINC01119 expression was increased in CAA-Exo, which could upregulate SOCS5 in OC. Finally, CAA-Exo carrying LINC01119 induced M2 polarization of macrophages to promote immune escape in OC, as evidenced by inhibited CD3 In conclusion, the key findings of the current study demonstrated the promoting effects of CAA-Exo containing LINC01119 mediating SOCS5 on M2 polarization of macrophages and immune escape in OC.

Hsa_circ_0001535 inhibits the proliferation and migration of ovarian cancer by sponging miR-593-3p, upregulating PTEN expression

Hsa_circ_0001535 is involved in biological processes in various tumors. However, the biological effects and related mechanism of hsa_circ_0001535 in ovarian cancer (OC) is unclear. This work is aimed to probe the biological function and underlying mechanism of hsa_circ_0001535 in OC, especially sponged with mi-RNA, require further elucidation. Hsa_circ_0001535 expression in OC tissues and cell lines were examined by qRT-PCR. Hsa_circ_0001535 overexpression model was constructed by lentivirus-mediated transfection in two OC cell lines, and the biological functions of hsa_circ_0001535 were evaluated by CCK-8, transwell assay and Western blot. Dual luciferase reporter gene assay was respectively used to explore the relationship between hsa_circ_0001535 and miR-593-3p, as well as miR-593-3p and PTEN. The expression of miR-593-3p and PTEN were detected by qRT-PCR in two OC cell lines and OC tissues. Hsa_circ_0001535 was down-regulated in OC tissues and cell lines. Hsa_circ_0001535 overexpression inhibited proliferation, migration and EMT marker expression in OC cells. Of interest, hsa_circ_0001535 targeted miR-593-3p and reduced its RNA level in OC cells. PTEN was a target gene of miR-593-3p, which was up-regulated by inhibiting miR-593-3p in OC cells. Furthermore, miR-593-3p mimic treatment reversed the up-regulation of PTEN by hsa_circ_0001535 overexpression in OC cells. The above results showed that hsa_circ_0001535 acted as a molecular sponge for miR-593-3p to repress miR-593-3p expression, and promoted the expression of PTEN, thus inhibited proliferation and migration of OC cells. Our research provides a potential therapeutic target for ovarian cancer patients.

Delivery of SIRT1 by cancer-associated adipocyte-derived extracellular vesicles regulates immune response and tumorigenesis of ovarian cancer cells

This study intends to investigate the possible molecular mechanism of immune response and tumorigenesis in ovarian cancer cells, mediated by sirtuin 1 (SIRT1)-containing extracellular vesicles (EVs) derived from cancer-associated adipocytes (CAAs) (CAA-EVs). Differentially expressed genes in EVs from CAAs were screened by RNA transcriptome sequencing, and the downstream pathway was predicted in silico. The binding between SIRT1 and CD24 was investigated by luciferase activity and ChIP-PCR assays. EVs were extracted from human ovarian cancer tissue-isolated CAAs, and the internalization of CCA-EVs by ovarian cancer cells was characterized. The ovarian cancer cell line was injected into mice to establish an animal model. Flow cytometry was performed to analyze the proportions of M1 and M2 macrophages, CD8 CAA-EVs could deliver SIRT1 to ovarian cancer cells, thereby affecting the immune response of ovarian cancer cells in vitro and promoting tumorigenesis in vivo. SIRT1 could transcriptionally activate the expression of CD24, and CD24 could up-regulate Siglec-10 expression. CAA-EVs-SIRT1 activated the CD24/Siglec-10 axis and promoted CD8 CAA-EVs-mediated transfer of SIRT1 regulates the CD24/Siglec-10 axis to curb immune response and promote tumorigenesis of ovarian cancer cells.

Organoid of ovarian cancer: genomic analysis and drug screening

AbstractOvarian cancer is the most common malignant tumors of the female reproductive system, and its standard treatments are cytoreductive surgery and platinum-based adjuvant chemotherapy. Great advances have been achieved in novel treatment strategies, including targeted therapy and immunotherapy. However, ovarian cancer has the highest mortality rate among gynecological tumors due to therapeutic resistance and the gap between preclinical data and actual clinical efficacy. Organoids are a 3D culture model that markedly affects gene analysis, drug screening, and drug sensitivity determination of tumors, especially when used in targeted therapy and immunotherapy. In addition, organoid can lead to advances in the preclinical research of ovarian cancer due to its convenient cultivation, good genetic stability, and high homology with primary tumors.

MMP11 and MMP17 are potential biomarkers for uterine corpus endometrial carcinoma prognosis

Matrix metalloproteinases (MMP) are important proteases that degrade the extracellular matrix (ECM) and thus essentially mediate tumor vascularization, metastasis, and invasion. However, their potential roles in uterine corpus endometrial carcinoma (UCEC) are not fully understood. The expression, prognostic value, and correlation of UCEC patients with MMP were investigated using data from The Cancer Genome Atlas (TCGA) and other databases. Furthermore, differentially expressed genes (DEGs) were identified and their biological functions and correlations with infiltrating immune cells were analyzed. A total of 22 MMPs were found to be abnormally expressed in UCEC tumor tissues, and high expression of MMP11 and MMP17 were associated with a better UCEC prognosis. MMP11 and MMP17 were observed to be significantly enriched in tumor tissue ECM and were associated with pathways involving degradation, glycolytic metabolism, and PI3K-Akt signaling. Infiltration of natural killer (NK), mast, and NK CD56bright cells was enhanced in tumor tissues with high MMP11 and MMP17 expression. MMP11 and MMP17 may affect UCEC prognosis by influencing immune cell infiltration and may be potential UCEC biomarkers.

Exclusive 3D-brachytherapy as a good option for stage-I inoperable endometrial cancer: a retrospective analysis in the gynaecological cancer GEC-ESTRO Working Group

Analyse outcomes of stage-I inoperable endometrial cancer (EC) patients from seven European centres treated with 3D-image-guided brachytherapy (IGBT) alone. From 2004 to 2018, 62 patients (41 stage-IA and 21 IB) were retrospectively studied, analysing anaesthetic procedure, applicator type, BT-planning imaging, clinical target volume (CTV), BT schedule, overall daily-dose equivalent to 2 Gy (EQD2 Mean follow-up: 32.8 months (SD 33.7). Spinal anaesthesia (38/62) followed by none (16/62) were the most common. Y-shaped Rotte applicators were used in 74% of patients. High-dose rate brachytherapy was administered in 89%. Median D90 to the CTV was 58.9 Gy (8.66-144 Gy). Eight patients presented relapse: four uterine, four nodal and four distant. The 2 and 5 year CSS was 93.3 and 80.5%, DFS 84.8 and 80.5%, LRFS was 93.1 and 88.7%, LRRFS was 91 and 91% and DMFS was 90.2 and 90.2%, respectively, CSS was better in stage-IA vs. IB (p = 0.043). Late vaginal and bladder G3-complication rates were 2.1%, respectively. Inoperable EC patients can be safely treated by BT with 2 and 5 year CSS of 93 and 80.5%, respectively, with even better results for IA cases. Prospective studies on 3D-IGBT are necessary to better analyse EC patient outcomes based on dose and treated volumes.

The impact of boost radiation therapy after hysterectomy on cervical cancer patients with close or positive resection margins

We investigated the effect of boost radiation therapy (RT) in addition to whole pelvis RT (WPRT) on treatment outcome and safety of cervical cancer patients following hysterectomy with close/positive resection margins (RM). We retrospectively analyzed 51 patients with cervical cancer who received WPRT with or without boost-RT as adjuvant treatment between July 2006 and June 2022. Twenty patients (39.2%) were treated with WPRT-alone, and 31 (60.8%) received boost-RT after WPRT using brachytherapy or intensity-modulated RT. The median follow-up period was 41 months. According to RT modality, the 4-year local control (LC) and locoregional control (LRC) rates of patients treated with WPRT-alone were 61% and 61%, respectively, whereas those in LC and LRC rates in patients who underwent WPRT with boost-RT were 93.2% and 75.3%, with p-values equal to 0.005 and 0.090, respectively. Seven patients (35.0%) had local recurrence in the WPRT-treated group compared to only two out of the 31 patients (6.5%) in the WPRT with boost-RT-treated counterparts (p = 0.025). Boost-RT was a significantly good prognostic factor for LC (p = 0.013) and LRC (p = 0.013). Boost-RT did not result in statistically-significant improvements in progression-free survival or overall survival. The acute and late toxicity rates were not significantly different between groups. Boost RT following WPRT is a safe and effective treatment strategy to improve LC without increasing toxicity in patients with cervical cancer with close/positive RM after hysterectomy.

Cervical carcinoma induces NLRP3 inflammasome activation and IL-1ß release in human peripheral blood monocytes affecting patients’ overall survival

Our group previously demonstrated that genetic variants in inflammasome genes contribute to protection against the establishment of human papilloma virus (HPV)-associated cervical carcinoma (CC). The objective of this study was to better understand the contribution of inflammasome and its cytokines in the CC microenvironment. The inflammasome activation was analyzed in CC tumoral cell lines and healthy donors (HD)' monocytes in co-culture. In vitro results were then compared to CC patients' public databases. CC cells did not produce IL-1ß or IL-18 themselves, however, when in co-culture with HD monocytes, induced IL-1ß release in those leucocytes. Inflammasome activation appears to be partially dependent on the NLRP3 receptor. Public data analysis revealed that IL1B expression is increased in the CC compared to normal uterine cervix, and that patients with high IL1B expression had a shorter overall survival. CC microenvironment can activate the inflammasome and IL-1ß release in surrounding monocytes, which could be detrimental for CC prognosis.

NPHS2-6 drives cervical squamous cell carcinoma (CSCC) progression via hsa-miR-1323/SMC1B axis to activate PI3K-Akt pathway

A substantial amount of evidence demonstrates suggests that long non-coding RNAs (lncRNAs) play a key role in the progression of various malignancies, cervical squamous cell carcinoma (CSCC) included. In our study, we deeply investigated the role and molecular mechanism of lncRNA NPHS2-6 in CSCC. The expression level of gene and protein expression were measured by qRT-PCR and western blot. To test the cell proliferation and cell metastasis ability, we carried out the CCK-8 experiment, clone formation assay, transwell assay and wound healing, respectively. The interactivity among NPHS2-6, miR-1323 and SMC1B were co demonstrated using the bioinformatics tool, dual-luciferase reporter system, and RNA pulldown assay. The subcutaneous tumor model of nude mice was established to verify the results of previous studies at the in vivo. NPHS2-6 was upregulated in CSCC tissues and cells. NPHS2-6 deficiency significantly inhibited CSCC cell growth and EMT in vitro. In addition, NPHS2-6 deficiency also inhibited the growth of CSCC xenograft tumors in mice in vivo. Importantly, NPHS2-6 was a competing endogenous RNA (ceRNA) to increases SMC1B levels by binding to miR-1323, leading to activate the PI3K/Akt pathway, thereby exacerbating tumorigenesis of CSCC. In conclusion, NPHS2-6/miR-1323/SMC1B/PI3K/Akt signaling accelerates the progression of CSCC, providing a new direction for the treatment strategy of CSCC.

Open-label phase II clinical trial of ketoconazole as CYP17 inhibitor in metastatic or advanced non-resectable granulosa cell ovarian tumors: the GREKO (GRanulosa Et KetOconazole) trial, GETHI 2011-03

Granulosa cell ovarian tumor (GCT) is characterized by a pathognomonic mutation in the FOXL2 gene (402 C > G) that leads to an overactivation of steroidogenesis. CYP17 is a key enzyme in such process and can be inhibited by ketoconazole. We designed a phase II clinical trial to assess the efficacy of ketoconazole in advanced GCT and conducted several in vitro studies to support the clinical findings. From October 1st 2012 to January 31st 2014, six evaluable patients were recruited in ten hospitals of the Spanish Group for Transversal Oncology and Research in Orphan and Infrequent Tumors" (GETTHI). FOXL2 (402C > G) mutation was confirmed in three; two cases were wild type and it could not be assessed in one. No objective response by RECIST was observed, but five cases achieved stable disease longer than 12 months. Median progression-free survival was 14.06 months (CI 95% 5.43-22.69) for the whole study population (3.38 and 13.47 months for wild-type cases and 14.06, 20.67 and 26.51 for those with confirmed FOXL2 mutation). Median overall survival was 22·99 months (CI 95% 8.99-36.99). In vitro assays confirmed the activity of ketoconazole in this tumor and suggested potential synergisms with other hormone therapies. Ketoconazole has shown activity in advanced GCT in clinical and in vitro studies. Based on these data, an orphan designation was granted by the European Medicines Agency for ketoconazole in GCT (EU/3/17/1857). NCT01584297.

Cancer-associated fibroblasts contribute to cancer metastasis and apoptosis resistance in human ovarian cancer via paracrine SDF-1α

Cancer-associated fibroblasts (CAFs), one of the main members of stromal cells in tumor microenvironment are proposed to play a central role in promoting tumor metastasis. It is unclear whether and how CAFs mediates tumor metastasis or chemoresistance in human ovarian cancer. CAFs were extracted from human ovarian cancer tissues (OCs) of patients with different kinds of histological types. We found that CAFs showed more aggressive potency than those tumor cells, both of which were isolated from the same ovarian cancer specimen. Moreover, when co-cultured with CAFs, cell migration abilities of ovarian cancer cells (SKOV3, OVCAR3 and HEY) were significantly increased. Next, we preliminarily detected a higher CAFs density in sections of metastatic lesions than those in primary tumor site of primary OCs clinically. However, no significant difference of stromal derived factors-1α (SDF-1α) production from CAFs was found between primary and metastatic lesions. Additionally, in contrast with tumor cells, CAFs exhibited obvious apoptosis resistance when treated with cisplatin. Furthermore, we found that cisplatin-induced cytotoxicity and apoptosis were significantly inhibited by co-cultured with recombinant human SDF-1α in SKOV3 in a time and dose-dependent manner, and this effect was suppressed by the CXCR4 antagonist AMD3100. CAFs might be involved in the malignant metastasis in human ovarian cancer through promoting cell migration in tumor cells. And their resistance to cytotoxic agents might be mediated by paracrine SDF-1α/CXCR4 signaling in ovarian cancer.

SEOM clinical guideline in ovarian cancer (2020)

AbstractDespite remarkable advances in the knowledge of molecular biology and treatment, ovarian cancer remains the leading cause of death from gynecologic cancer. In the last decade, there have been important advances both in systemic and surgical treatment. However, there is no doubt that the incorporation of PARP inhibitors as maintenance after the response to platinum-based chemotherapy, first in recurrent disease and recently also in first line, will change the natural history of the disease.The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of ovarian cancer, and to provide evidence-based recommendations for clinical practice.

Recommendations of the Spanish brachytherapy group of the Spanish Society of Radiation Oncology and the Spanish Society of Medical Physics for interstitial high-dose-rate brachytherapy for gynaecologic malignancies

Abstract The present document includes consensus-based recommendations from the Brachytherapy Group (GEB) of the Spanish Society of Radiation Oncology (SEOR) and the Spanish Society of Medical Physics (SEFM) for interstitial high-dose-rate (HDR) brachytherapy (BT) for gynaecologic malignancies. A nine-item survey—which included questions on experience with interstitial BT; indications and technique; applicator type; magnetic resonance imaging (MRI)-based planning; dose; fractionation schedule; and treatment planning—was sent to all radiation oncology departments ( n  = 174) in Spain in 2021. Responses were received from 36 centres (50% of all centres [ n  = 72] with a BT unit). The consensus-based recommendations presented here are based on a review of the available literature, professional experience among the group of experts, and in-person discussions held during the annual meeting of these two societies. We describe the results of the survey and the following: indications; contraindications; patient selection; description of applicators; role of imaging in planning; contouring; dose prescription; dosimetric reconstruction; optimisation; and dose indications for cancers of the cervix, vagina, and vulva. The various clinical scenarios in which interstitial BT is used in the treatment of gynaecological tumours are described in detail, including cervix intracavitary/interstitial hybrid HDR-BT; cervix perineal templates/freehand implants; primary vaginal malignancies/vaginal recurrences; and vulvar interstitial implants.

MiR-92 overexpression suppresses immune cell function in ovarian cancer via LATS2/YAP1/PD-L1 pathway

Increasing evidence suggested that microRNA plays an important role in ovarian cancer. In this study, the role of miR-92 in ovarian cancer was investigated. In this study, miR-92 expression in clinical sample was evaluated, role of miR-92 was investigated in vitro, and underlying mechanism was investigated using Chip, co-IP, and western blot. In this study, we show that miR-92 is overexpressed in ovarian cancer tissue compared with normal cancer tissue. Transfection of miR-92 increased proliferation of ovarian cancer cell, and increased migration capacity and colony formation were observed after miR-92 transfection; we found that expression of LATS2 was decreased by miR-92, and this was further confirmed by luciferase assay, which proved that miR-92 is targeting 3' of the endogenous LATS2 gene. Downregulation of LATS2 resulted in increased translocation of YAP1 and upregulation of PD-L1, which subsequently suppressed NK cell function and promoted T cell apoptosis. Moreover, co-transfection of YAP1-targeted shRNA could relieve miR-92-induced immune suppression effect. Mechanically, immunoprecipitation (IP) was used to show that LATS2 interacted with YAP1 and subsequently limited nuclear translocation of YAP1; chromatin immunoprecipitation (ChIP) was used to confirm that YAP1 could bind to enhancer region of PD-L1 to enhance transcription activity of PD-L1. Our data revealed a novel mechanism which finally resulted in immune suppression in ovarian cancer.

Bevacizumab in recurrent ovarian cancer: could it be particularly effective in patients with clear cell carcinoma?

Treatment of recurrent ovarian carcinoma is a challenge, particularly for the clear cell (CCC) subtype. However, there is a preclinical rationale that these patients could achieve a benefit from antiangiogenic therapy. To assess this hypothesis, we used the growth modulation index (GMI), which represents an intrapatient comparison of two successive progression-free survival (PFS). We conducted a retrospective real-world study performed on 34 patients with recurrent ovarian cancer, treated with bevacizumab-containing regimens from January 2009 to December 2017. The primary endpoint was GMI. An established cut-off > 1.33 was defined as a sign of drug activity. 73.5% of patients had high-grade serous ovarian carcinoma (HGSOC), and 17.7% had CCC; 70.6% of patients received carboplatin/gemcitabine/bevacizumab, and 29.4% received weekly paclitaxel/bevacizumab. According to histological subtype, the overall response rate and median PFS were 52% and 14 months for HGSOC and 83.3% and 20 months for CCC, respectively. The overall population median GMI was 0.99; it was 0.95 and 2.36 for HGSOC and CCC, respectively. CCC subtype was significantly correlated with GMI > 1.33 (odds ratio 41.67; 95% confidence interval 3.6-486.94; p = .03). Adding bevacizumab to chemotherapy in recurrent CCC is associated with a remarkable benefit in this cohort. The efficacy of antiangiogenic drugs in CCC warrants further prospective evaluation.

miR-22 suppresses cell viability and EMT of ovarian cancer cells via NLRP3 and inhibits PI3K/AKT signaling pathway

miR-22 plays a great role in inhibiting cell growth, metastasis and enhanced cell apoptosis in several cancers. The purpose of this study was to investigate the functions of miR-22 in ovarian cancer. The proliferative ability was measured using CCK-8 assay. The protein expression associated with EMT and PI3K/AKT signaling biomarkers were measured by western blot. Luciferase assay applied to measure the luciferase activity. Kaplan-Meier method was performed to evaluate the overall survival rate of ovarian cancers. miR-22 was low expressed and NLRP3 was overexpressed in ovarian cancer tissues and cells, and downregulation of miR-22 was associated with poor prognosis. The expression of NLRP3 had a negative correlation with miR-22 expression in ovarian cancer. miR-22 promoted cell viability and EMT through directly binding to the 3'-UTR of NLRP3 mRNA and inhibited PI3K/AKT signaling pathway. NLRP3 partially restored functions of miR-22 on cell proliferation and EMT in ovarian cancer. miR-22 impaired cell viability and EMT by NLRP3 and inhibited PI3K/AKT signaling pathway in ovarian cancer. The newly identified miR-22/NLRP3/PI3K/AKT axis provides novel insight into the pathogenesis of ovarian cancer.

Evaluating the benefits of immunotherapy in metastatic cervical cancer: an observational retrospective analysis

Abstract Background Cervical cancer is the fourth most commonly diagnosed cancer and the fourth leading cause of cancer-related death in women globally. Recent advances in immunotherapy have demonstrated promising results. This study analyses the real-world impact of adding immunotherapy for patients with stage IV cervical carcinoma. Material and methods This longitudinal retrospective observational study included patients with stage IV cervical carcinoma in the first metastatic setting treated between 2010 and 2023 at the University Hospital Nuestra Señora de Candelaria in Tenerife, Spain. To evaluate the primary objective, patients were divided into two groups depending on whether they had received immunotherapy with pembrolizumab or not. The primary endpoint was 12-month progression-free survival in patients receiving immunotherapy compared to those not receiving it. Results A total of 56 patients were analyzed, of whom 31 were tested for PD-L1. Among those tested, 25 patients (84%) were PD-L1 positive, and 18 of them (72%) received immunotherapy. The objective response rate was significantly higher, being 94% in the group that received immunotherapy, compared to 32% in the group that did not (p &lt; 0.001). At 12 months, the cumulative probability of progression-free survival was estimated at 94.4% for the immunotherapy group versus 59.7% in the non-immunotherapy group (p = 0.009), with a hazard ratio of 0.116 (CI95%: 0015 – 0.883; p = 0.038). Immunotherapy alone or combined with bevacizumab showed similar progression-free survival probabilities. However, these outcomes were significantly different when compared to patients who received neither therapy (p &lt; 0.001). Conclusions Our findings confirm that immunotherapy significantly improves progression-free survival and objective response rates in metastatic cervical carcinoma, aligning with the results from the KEYNOTE-826 trial. The implementation of PD-L1 testing and the addition of immunotherapy whenever possible are challenges to be achieved in clinical practice.

Spanish Society for Radiation Oncology and Spanish Society of Medical Physicists recommendations on reirradiation in gynecological cancer: reirradiation techniques, survival outcomes, dose, and toxicity

Reirradiation in gynecological cancer presents significant clinical challenges due to the complexities of prior treatments and anatomical constraints. In response to the lack of standardized protocols, a Delphi-based consensus was conducted by the GINECOR group of the Spanish Society of Radiation Oncology (SEOR) and the Spanish Society of Medical Physics (SEFM). A multidisciplinary panel of radiation oncologists and medical physicists developed expert-based recommendations through a structured tow-round process. Key findings emphasize the pivotal role of brachytherapy for central and vaginal recurrences and support the use of stereotactic body radiation therapy (SBRT) for nodal disease. Other modalities such as intraoperative radiotherapy and proton therapy are considered in specialized settings. The consensus highlights the importance of individualized treatment planning, especially regarding cumulative dose constraints and organ-at-risk tolerance. Futhermore, it underscores the need for further research and prospective clinical trials to refine treatment indications and optimize outcomes in this clinical context.

Sexual, bladder and bowel function following different minimally invasive techniques of radical hysterectomy in patients with early-stage cervical cancer

Abstract Purpose Despite the establishment of radical surgery for therapy of cervical cancer, data on quality of life and patient-reported outcomes are scarce. The aim of this retrospective cohort study was to evaluate bladder, bowel and sexual function in women who underwent minimally invasive surgery for early-stage cervical cancer. Methods From 2007–2013, 261 women underwent laparoscopically assisted radical vaginal hysterectomy (LARVH = 45), vaginally assisted laparoscopic or robotic radical hysterectomy (VALRRH = 61) or laparoscopic total mesometrial resection (TMMR = 25) and 131 of them completed the validated German version of the Australian Pelvic Floor Questionnaire (PFQ). Results were compared with controls recruited from gynecological clinics (n = 24) and with urogynecological patients (n = 63). Results Groups were similar regarding age, BMI and parity. The TMMR group had significantly shorter median follow-up (16 months versus 70 and 36 months). Postoperatively, deterioration of bladder function was reported by 70%, 57% and 44% in the LARVH, VARRVH and TMMR groups, respectively (p = 0.734). Bowel function was significantly worse after TMMR with a higher deterioration rate in 72 versus 43% (LARVH) and 47% (VARRVH) with a correspondingly higher bowel dysfunction score of 2.9 versus 1.5 and 1.8, respectively and 1.8 in urogynaecological patients. Sexual dysfunction was common in all surgical groups. 38% considered their vagina too short which was significantly associated with deep dyspareunia. Compared with controls, surgical groups had significantly increased PFQ scores. Conclusion Pelvic floor dysfunction commonly deteriorates and negatively impacts on quality of life after minimally invasive radical hysterectomy, especially bowel function after TMMR. Pelvic floor symptoms should routinely be addressed pre- and postoperatively.

The expression of corticotropin-releasing hormone family peptides in premalignant and malignant vulvar lesions

Abstract Objectives To examine the relation of corticotropin-releasing hormone (CRH) family peptides with inflammatory processes and oncogenesis, emphasizing in vulvar inflammatory, premalignant and malignant lesions, as well as to investigate the possibility of lesion cells immunoescaping, utilizing FAS/FAS-L complex. Methods Immunohistochemical expression of CRH, urocortin (UCN), FasL and their receptors CRHR1, CRHR2 and Fas was studied in vulvar tissue sections obtained from patients with histologically confirmed diagnosis of lichen, vulvar intraepithelial neoplasia (VIN) and vulvar squamous cell carcinoma (VSCC). The patient cohort was selected from a tertiary teaching Hospital in Greece, between 2005 and 2015. For each of the disease categories, immunohistochemical staining was evaluated and the results were statistically compared. Results A progressive increase of the cytoplasmic immunohistochemical expression of CRH and UCN, from precancerous lesions to VSCC was observed. A similar increase was detected for Fas and FasL expression. Nuclear localization of UCN was demonstrated in both premalignant and VSCC lesions, with staining being significantly intensified in carcinomas, particularly in the less differentiated tumor areas or in the areas at invasive tumor front. Conclusions Stress response system and CRH family peptides seem to have a role in inflammation maintenance and progression of vulvar premalignant lesions to malignancy. It seems that stress peptides may locally modulate the stroma through Fas/FasL upregulation, possibly contributing to vulvar cancer development.

Discontinuation of mechanical bowel preparation in advanced ovarian cancer surgery: an enhanced recovery after surgery (ERAS) initiative

To investigate the impact of discontinuation of mechanical bowel preparation in advanced ovarian cancer surgery within the context of the ERAS program. We retrospectively reviewed the medical records of patients with advanced ovarian cancer who underwent cytoreductive surgery with simultaneous colon and/or rectal resection from January 2012 to November 2020. Patients were divided into two groups based on whether preoperative mechanical bowel preparation (MBP) was given (pre-ERAS) or not (post-ERAS). Patient characteristics, including duration of antibiotic treatment, surgical complexity, and incidence of surgical and nonsurgical complications, were compared. During the study period, 114 patients who underwent colon and/or rectal resection were examined, of whom 39 received MBP and 75 did not receive MBP (NMBP). On comparison between the two groups, no significant differences were noted in the assessed patient characteristics, including mean age, FIGO stage, ASA class, BMI, or residual tumor. One patient (2.6%) in the MBP group, and 4 patients (5.3%) in the NMBP group experienced an anastomotic leakage (p = 0.11). No significant differences were found with respect to surgical site infection. (p = 0.5). MBP was not associated with any specific benefit for advanced ovarian cancer surgery. Gynecologic oncologists who use MBP should consider discontinuing this practice.