Search Results (143)

Uterine leiomyomas or fibroids, are non-cancerous smooth muscle proliferations of the uterus, occurring mostly in women of reproductive age. Their pathogenesis involves complex growth factor interactions that regulate cellular proliferation, extracellular matrix (ECM) remodeling, and angiogenesis in myometrium. Women affected by fibroids often have a range of consequences such as infertility, endometriosis, and dysmenorrhea. Several growth factors such as vascular endothelial growth factor (VEGF), transforming growth factor (TGF-β), and platelet-derived growth factors (PDGF) have long been described as key regulators of angiogenic and fibrotic activities in fibroid tissue. Moreover, we summarized updated information between 2015 and 2025 following strictly inclusion/exclusion criteria and key research areas, including growth factors and its isoform-interaction, their roles within key signaling pathways, and the contribution of ECM deposition in uterine fibroids development and growth. Implementing growth factors in the clinical research field can develop new biomarkers and treatment options, focusing on effective and advanced management of uterine fibroids. Full article

Background/Objectives: Although the binarism between type I and II endometrial cancer was dismissed and substituted with molecular classification, histopathological features remain of paramount importance. Hence, analysing survival outcomes according to histological type, our aim is to clarify whether the morphological features of the tumour retain prognostic relevance in the context of advanced disease. Methods: This is a retrospective analysis led within the Thames Valley Cancer Alliance Network. Results: We include 148 FIGO 2009 stage III–IV patients affected by endometrioid endometrial cancer (EEC) G1, G2, and G3, carcinosarcoma (CS), serous carcinoma (SC), and clear cell carcinoma (CCC) of the uterus. Five year overall survival (OS) is distinct among the histological groups (p-value < 0.001), being 73.3% for G2 endometrioid, 49.2% for G3 endometrioid, 8.3% for CS, and 28.4% for SC. The divergence was marked also for 5 year progression-free survival (PFS) (p-value < 0.001) as follows: for G2 endometrioid, was 76.4%; for G3 endometrioid, 52.7%; and for carcinosarcoma, 5.9%. PFS after 18 months for serous carcinoma was 5.7%. The multivariate analysis found G3 endometrioid (HR 2.91, 95% CI 1.20–7.11, p-value 0.018), carcinosarcoma (HR 12.15, 95% CI 5.07–29.11, p-value < 0.001), and serous carcinoma (HR 4.84, 95% CI 2.16–10.83, p-value < 0.001) as independent predictors of poor survival, as well as cervical invasion (HR 1.83, 95% CI 1.10–3.05, p-value 0.020) as the only histopathological feature confirmed. Regarding progression-free only carcinosarcoma (HR 14.91, 95% CI 5.28–41.11) and serous carcinoma (HR 17.68, 95% CI 6.41–48.75) were associated with an increased risk of recurrence. Conclusions: Our findings testify that, beyond the disease stage, histological subtype remains a major determinant of survival outcome. Cervical involvement is associated with a more aggressive disease, possibly correlated to death beyond relapse. Prospective trials involving advanced stage endometrial cancer, stratified by histological subtype and integrated with the molecular classification, are required. Full article

Background/Objectives: Endometrial hyperplasia (EH) is a pathology of the uterus, which is a pathological overgrowth of the endometrial glands associated with the risk of progression to endometrial cancer (EC). The purpose of this study was to conduct a retrospective comparative analysis of the medical and social characteristics of women with endometrial hyperplasia (EH) across two time periods (2016–2017 and 2023–2024) in Almaty, the largest city in Kazakhstan. Methods: A retrospective comparative analysis included 376 women (188 per period) with histologically confirmed EH treated in public and private healthcare facilities. Data were extracted from electronic medical systems (Damumed, Avicenna). Group differences were evaluated using the χ² test, Fisher’s exact test, and Mann–Whitney U test. Odds ratios (OR) with 95% confidence intervals (CI) were calculated; significance was set at p < 0.05. Results: The proportion of postmenopausal women increased from 22.3% to 37.8% (OR: 2.11, 95% CI: 1.34–3.32, p < 0.001), and self-referrals to private clinics rose from 17.6% to 37.2% (OR: 2.79, 95% CI 1.73–4.49, p < 0.001). Women with higher education became more prevalent (from 26.1% to 43.6%, OR: 2.19, 95% CI: 1.42–3.39, p < 0.001), along with an increase in endocrine and metabolic disorders such as thyroid disease (from 4.8% to 12.2%, OR: 2.77, 95% CI: 1.25–6.16) and overweight status (from 51.6% to 65.4%, OR: 1.78, 95% CI: 1.17–2.69, p = 0.020). Asymptomatic cases were more frequently detected (from 18.6% to 28.2%, OR: 1.72, CI: 1.06–2.79, p = 0.028), and diagnostic approaches shifted from blind curettage (78.2% vs. 47.3%, OR: 0.25, CI: 0.16–0.39, p < 0.001) toward hysteroscopy with biopsy (from 21.3% to 53.7%, OR: 4.30, CI: 2.73–6.75, p < 0.001). Conclusions: Over seven years, the clinical and socio-demographic composition of women with EH in Almaty has changed toward older, more educated, and metabolically burdened populations, with broader access to minimally invasive diagnostic methods. The findings describe observable structural changes and risk group patterns, emphasizing the importance of prospective, registry-based, and molecularly oriented studies to refine clinical strategies for prevention and early detection. Full article

Genetic abnormalities of the fibroblast growth factor receptor 2 (FGFR2) gene, including amplification, fusions, and mutations, have been reported in various solid tumors. While molecular targeted therapies against FGFR2 fusion have been proved to be useful in cholangiocarcinoma, the therapeutic significance of FGFR2 inhibitors remains unclear in other various solid cancers. Genomic and clinical information from solid tumor cancer gene panel testing cases is consolidated in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database in Japan. This study aimed to utilize the C-CAT database to clarify the clinical–pathological significance of FGFR2 abnormalities. A total of 101,231 patients with solid cancer have been registered in the C-CAT database between June 2019 and June 2025. Of the 101,231 cases, 1312 cases with FGFR2 gene abnormalities were analyzed. FGFR2 alterations included amplification in 515 cases, fusion in 280 cases, and mutations in 568 cases. They were detected most frequently in the biliary tract (271 cases), esophagus/stomach (231 cases), and breast (211 cases). Amplification was frequent in the esophagus/stomach (205 cases) and breast (105 cases). Mutations were frequent in the uterus (111 cases), breast (89 cases), and biliary tract (86 cases). Among 515 FGFR2 alteration cases, FGFR2 inhibitors were administered in 85 cases. Of the 85 cases, disease control was achieved in 49 cases, 44 cases of which were biliary tract cancer. FGFR2 might be a promising therapeutic target not only for cholangiocarcinoma with fusion but also for esophagus/stomach cancer and breast cancer with FGFR2 alterations. Full article

Background/Objectives: This study aims to critically appraise the role of para-aortic surgical staging in locally advanced cervical cancer (LACC) in the era of advanced imaging, and to outline how selective surgery and biomarkers could be integrated within modern, quality-assured treatment pathways. Methods: Narrative review of randomized trials, large databases, and prospective/retrospective series comparing para-aortic lymphadenectomy with imaging-based staging; focused appraisal of Uterus-11, NCDB analyses, and ongoing prospective trials (PAROLA with Senti-PAROLA as one of its sub-studies and PALDISC). Emerging technologies (PET/MRI, radiomics/AI) and molecular assays (OSNA, HPV-ctDNA) were also assessed. Results: PET/CT remains the standard for distant staging, but sensitivity for low-volume nodal disease (<5 mm) is poor; in pelvic-positive/para-aortic-negative patients, occult para-aortic metastases approach ~21%. Para-aortic surgical staging modifies radiotherapy planning in ~18% of cases and can act as a de-escalation tool by avoiding unnecessary extended-field CRT (EF-CRT) when para-aortic nodes are negative. Uterus-11 showed no overall survival difference versus CT-based staging, but suggested benefit in FIGO 2009 stage IIB; its design (CT comparator, optimistic assumptions, limited power) constrains inference. Minimally invasive extraperitoneal/transperitoneal staging is feasible with low morbidity in expert centers, yet real-world management may worsen outcomes. The role of systemic intensification in node-positive disease remains undefined: PALN-positive patients were excluded from the INTERLACE trial. In the KEYNOTE-826 study, subgroup analyses according to nodal status were not reported, although the benefit of pembrolizumab remained consistent irrespective of bevacizumab use. Sentinel para-aortic mapping and biomarkers (e.g., HPV-ctDNA) may refine selection and reduce morbidity. Conclusions: Surgical staging is the most accurate method to detect occult para-aortic disease. Its routine use is not justified, but it may benefit selected high-risk patients, particularly where decisions on EF-CRT or systemic therapy hinge on para-aortic status. Future practice should integrate advanced imaging, selective surgery, and biomarkers within accredited centers, guided by large collaborative trials conducted under international quality frameworks such as ESGO/ESTRO/ESP guidelines. Full article

Endometrial cancer is one of the most common malignancies of the female reproductive system, with incidence rising globally due to population ageing and life-style-related risk factors. Calcium (Ca²⁺) is a ubiquitous second messenger regulating diverse physiological processes, and its dysregulation has been increasingly implicated in carcinogenesis, including endometrial. Altered expression and function of Ca²⁺ channels, pumps, exchangers, and binding proteins disrupt the finely tuned balance of Ca²⁺ influx, efflux, and intracellular storage, leading to aberrant signalling that promotes tumour proliferation, migration, survival, and metastasis. This review summarises current knowledge on the molecular “Ca²⁺ toolkit” in the human uterus, highlighting the role of voltage-gated calcium channels (VGCCs), transient receptor potential (TRP) channels, store-operated calcium entry (SOCE) components, Na⁺/Ca²⁺ exchangers, purinergic receptors, P-type ATPases (SERCA, SPCA, PMCA), ryanodine (RyR) and inositol 1,4,5-trisphosphate (IP₃R) receptors, and mitochondrial Ca²⁺ uniporter (MCU) complexes in endometrial cancer progression. Multiple Ca²⁺-handling proteins, including CACNA1D, CACNA2D1, TRPV4, TRPV1, TRPM4, MCU, and RyR1, exhibit cancer-associated overexpression or functional changes, correlating with poor prognosis and aggressive disease features. Emerging evidence supports the therapeutic potential of targeting Ca²⁺ homeostasis using small-molecule inhibitors, ion channel modulators or gene-silencing strategies. These interventions may restore Ca²⁺ balance, induce apoptosis or autophagy, and suppress metastatic behaviour. While no clinical trials have yet explicitly focused on Ca²⁺ modulation in endometrial cancer, the diversity of dysregulated Ca²⁺ pathways offers a rich landscape for novel therapeutic strategies. Targeting key components of the Ca²⁺ signalling network holds promise for improving outcomes in endometrial cancer. Full article

The female reproductive system represents a highly complex regulatory network governing critical physiological functions, encompassing reproductive capacity and endocrine regulation that maintains female physiological homeostasis. The in vitro simulation system provides a novel tool for biomedical research and can be used as physiological and pathological models to study the female reproductive system. Recent advances in this technology have evolved from 2D and 3D printing to organ-on-a-chip (OOC) and microfluidic systems, which has emerged as a transformative platform for modeling the female reproductive system. These microphysiological systems integrate microfluidics, 3D cell culture, and biomimetic scaffolds to replicate key functional aspects of reproductive organs and tissues. They have enabled precise simulation of hormonal regulation, embryo-endometrium interactions, and disease mechanisms such as endometriosis and gynecologic cancers. This review highlights the current state of female reproductive OOCs, including ovary-, uterus-, and fallopian tube-on-a-chip system, their applications in assisted reproduction and disease modeling, and the technological hurdles to their widespread application. Though significant barriers remain in scaling OOCs for high-throughput drug screening, standardizing protocols for clinical applications, and validating their predictive value against human patient outcomes, OOCs have emerged as a transformative platform to model complex pathologies, offering unprecedented insights into disease mechanisms and personalized therapeutic interventions. Future directions, including multi-organ integration for systemic reproductive modeling, incorporation of microbiome interactions, and clinical translation for mechanisms of drug action, will facilitate unprecedented insights into reproductive physiology and pathology. Full article

Endometrial hyperplasia, presenting without atypia (EH) or as atypical hyperplasia (AH), is considered a precursor of endometrial cancer and affects women of reproductive or perimenopausal age, posing a major public health concern. The aim of this study was to review and compare the most recently published influential guidelines providing recommendations on the management of endometrial hyperplasia. Thus, a comparative review of guidelines from the Royal College of Obstetricians and Gynecologists, the Society of Obstetricians and Gynecologists of Canada, and the American College of Obstetricians and Gynecologists was conducted. There is a consensus regarding the optimal management strategies for EH, with observation and medical treatment being the first-line options and surgical treatment with total hysterectomy offering a second line in specific cases. Moreover, there is agreement regarding patients with AH, with surgical treatment being the recommended approach, while medical therapy is preferred for women who seek fertility preservation. Notably, close surveillance with endometrial biopsies every 3 or 6 months is suggested unanimously, as well as long-term follow-up in high-risk patients. Controversy exists regarding the initial diagnostic approach, with RCOG and SOGC suggesting outpatient endometrial biopsy, while ACOG recommends diagnostic hysteroscopy, as well as the therapeutic regimens for the oral treatment of EH. Surgical techniques such as endometrial ablation, intraoperative frozen section analysis, intraoperative visual inspection of the uterus, and morcellation constitute areas of controversy among the reviewed guidelines, and the surveillance protocols for women with EH are addressed differently between RCOG and SOGC. Notably, RCOG is the only medical society offering recommendations regarding women under HRT and those on therapy for breast cancer. The development of consistent international practice protocols for timely management strategies and surveillance protocols is of paramount importance to safely guide clinical practice and subsequently improve women’s health. Full article

Endometriosis is a complex gynecological condition affecting 10% of women globally, characterized by the growth of endometrial-like tissue outside the uterus, leading to chronic pelvic pain, infertility, reduced quality of life, and a risk of cancer. This review examines the multifaceted aspects of endometriosis, including its causes, diagnostic approaches, and management strategies. Genetic and environmental factors, hormonal influences, and immunological dysregulation are addressed as potential drivers of disease progression. Treatment options, including pharmacological interventions (hormone therapy, pain management) and surgical interventions, are assessed for their effectiveness in alleviating symptoms and improving outcomes. Emerging therapies, such as small-molecule inhibitors and anti-angiogenic agents, are also explored. Additionally, the psychological impact of endometriosis is addressed, emphasizing the need for holistic care. This review highlights the importance of continued research to unravel the precise mechanisms underlying endometriosis and to develop targeted therapies for improved patient care. Full article

Backgroud. Endometriosis is a chronic, estrogen-dependent inflammatory disease characterized by the ectopic presence of endometrial-like tissue. Although genome-wide association studies (GWAS) have identified susceptibility variants, their tissue-specific regulatory impact remains poorly understood. Objective. To functionally characterize endometriosis-associated variants by exploring their regulatory effects as expression quantitative trait loci (eQTLs) across six physiologically relevant tissues: peripheral blood, sigmoid colon, ileum, ovary, uterus, and vagina. Methods. GWAS-identified variants were cross-referenced with tissue-specific eQTL data from the GTEx v8 database. We prioritized genes either frequently regulated by eQTLs or showing the strongest regulatory effects (based on slope values, which indicate the direction and magnitude of the effect on gene expression). Functional interpretation was performed using MSigDB Hallmark gene sets and Cancer Hallmarks gene collections. Results. A tissue specificity was observed in the regulatory profiles of eQTL-associated genes. In the colon, ileum, and peripheral blood, immune and epithelial signaling genes predominated. In contrast, reproductive tissues showed the enrichment of genes involved in hormonal response, tissue remodeling, and adhesion. Key regulators such as MICB, CLDN23, and GATA4 were consistently linked to hallmark pathways, including immune evasion, angiogenesis, and proliferative signaling. Notably, a substantial subset of regulated genes was not associated with any known pathway, indicating potential novel regulatory mechanisms. Conclusions. This integrative approach highlights the com-plexity of tissue-specific gene regulation mediated by endometriosis-associated variants. Our findings provide a functional framework to prioritize candidate genes and support new mechanistic hypotheses for the molecular pathophysiology of endometriosis. Full article

Species belonging to the genus Cnidoscolus have been widely recognized for their diverse applications, including forage, oil production, latex, ornamental purposes, medicinal uses, and as nutritional sources. This study aimed to compile up-to-date information on the chemical, nutritional, and ethnopharmacological aspects, as well as the biological activities, of Cnidoscolus species, offering a critical overview of the current advancements in research on these plants. The reviewed literature indicates that Cnidoscolus species hold significant traditional use value, particularly in the treatment of conditions such as cancer, diabetes, and disorders affecting the uterus, prostate, ovaries, and kidneys, in addition to menstrual disturbances, inflammation, and general pain. Scientifically, their efficacy has been demonstrated in several contexts, including antinociceptive, antibacterial, anti-inflammatory, cytotoxic, antiproliferative, hypoglycemic, and antioxidant activities, among others. Additionally, certain species like C. aconitifolius have shown potential for human consumption, with leaves being eaten raw or cooked, while C. quercifolius demonstrates nutritional value in its seeds, which can be utilized in the development of functional foods. However, further studies are needed to focus on the isolation and characterization of bioactive compounds found in these species, as well as deeper investigations into the molecular and cellular mechanisms underlying their biological activities and assessments of the safety of long-term consumption in both humans and animals. Moreover, more extensive clinical and preclinical studies are essential to validate the proposed therapeutic effects and to support the safe and effective inclusion of these species in conventional treatment regimens. Full article

Cancer of the uterine cervix (cervical cancer) is a leading cancer among women worldwide, although its incidence has been reducing in many developing nations. In the majority of cervical cancer cases, the presence of high-risk human papillomavirus (HPV) is usually detected. However, a growing body of evidence currently considers that exclusive HPV infection may not be sufficient for cancer development. Apart from certain common risk factors for cervical cancer, like poor nutritional status and smoking, many studies documented an association with other viral infections, such as human immunodeficiency virus (HIV) and herpes simplex virus type 2 (HSV-2). Similarly, vaginal bacterial populations perhaps play a key role in cervical cancer. It may be worth mentioning that different bacterial species can immensely influence (either protecting or adversely) the biochemical characteristics of the cervicovaginal environment—for example, Lactobacillus crispatus, Gardnerella vaginalis, and Chlamydia trachomatis. As a result, chronic infections with unfavorable microorganisms (other than HPV) may affect the pathological processes of malignancy. On the other hand, the cervix is an estrogen-sensitive organ like the corpus uteri (i.e., the body of the uterus). Estrogen and different estrogen receptors are implicated in the development and promotion of various cancers, including endometrial cancer. A number of reports also suggest a close association between estrogen and HPV in the development of cervical cancer. Furthermore, estrogen is linked with the characteristics of the vaginal microenvironment including bacteria. Therefore, several of the abovementioned factors (some are preventable) could play an important role in the progression of cervical neoplastic lesions. Full article

Background/Objectives: To develop a nomogram for predicting tumor aggressiveness and the presence of lymphovascular space involvement (LVSI) in patients with endometrial cancer (EC) using preoperative MRI and pathology–laboratory data. Methods: This IRB-approved, retrospective, multicenter study included 245 patients with histologically confirmed EC who underwent preoperative MRI and surgery at participating institutions between January 2020 and December 2024. Tumor type and grade, both from preoperative biopsy and surgical specimens, as well as preoperative CA125 and HE4 levels, were retrieved from institutional databases. A preoperative MRI was used to assess tumor morphology (polypoid vs. infiltrative), maximum diameter, presence and depth (< or >50%) of myometrial invasion, cervical stromal invasion (yes/no), and minimal tumor-to-serosa distance. The EC-to-uterus volume ratio was also calculated. Results: Among the 245 patients, 27% demonstrated substantial LVSI, and 35% were classified as aggressive on final histopathology. Multivariate analysis identified independent MRI predictors of LVSI, including cervical stromal invasion (OR = 9.06; p = 0.0002), tumor infiltration depth (OR = 2.09; p = 0.0391), and minimal tumor-to-serosa distance (OR = 0.81; p = 0.0028). The LVSI prediction model yielded an AUC of 0.834, with an overall accuracy of 78.4%, specificity of 92.2%, and sensitivity of 43.1%. For tumor aggressiveness prediction, significant predictors included biopsy grade (OR = 8.92; p < 0.0001), histological subtype (OR = 12.02; p = 0.0021), and MRI-detected serosal involvement (OR = 14.39; p = 0.0268). This model achieved an AUC of 0.932, with an accuracy of 87.0%, sensitivity of 79.8%, and specificity of 91.2%. Both models showed excellent calibration (Hosmer–Lemeshow p > 0.86). Conclusions: The integration of MRI-derived morphological and quantitative features with clinical and histopathological data allows for effective preoperative risk stratification in endometrial cancer. The two nomograms developed for predicting LVSI and tumor aggressiveness demonstrated high diagnostic performance and may support individualized surgical planning and decision-making regarding adjuvant therapy. These models are practical, reproducible, and easily applicable in standard clinical settings without the need for radiomics software, representing a step toward more personalized gynecologic oncology. Full article

Endometriosis is a chronic gynecological disorder characterized by the presence of endometrial-like tissue outside the uterus, leading to inflammation, pain, and infertility. Emerging evidence indicates that endometriotic lesions exhibit cancer-like properties, including metabolic reprogramming marked by increased glucose uptake, enhanced Warburg’s effect, and altered mitochondrial function. These metabolic adaptations support cell survival under hypoxic conditions and contribute to immune evasion and sustained proliferation. This review summarizes current findings on the molecular mechanisms driving metabolic reprogramming in endometriosis, including the roles of mitochondrial dysfunction, hypoxia-inducible factor (HIF) signaling, the PI3K/AKT/mTOR pathway, inflammatory cytokines, and genetic and epigenetic regulators. In addition, we discuss therapeutic strategies targeting glycolytic pathways using both synthetic inhibitors and natural compounds, which represent promising non-hormonal options. Finally, we highlight the need for further preclinical and clinical studies to validate metabolic interventions and improve outcomes for patients with endometriosis. Full article

Endometriosis is a gynecological disease characterized by the presence of endometrium-like cells located outside the uterus. The most widely accepted theory for endometriosis development, retrograde menstruation, does not account for extra-pelvic lesions or ones found on other organs in the peritoneal cavity. Similar to ovarian cancer, endometriosis cells can interact with the mesothelial cells of the peritoneal cavity. In ovarian cancer metastasis, ovarian cancer cell spheroids attach and push away the mesothelial cells lining the peritoneal cavity, clearing the mesothelial layer. Since endometriosis cells are known to interact with the mesothelium, we hypothesized that endometriosis cells would be able to form spheroids capable of undergoing mesothelial clearance. To test this, we designed an in vitro mesothelial clearance assay using endometriosis spheroids and a mesothelial cell monolayer. Our results demonstrate that normal and endometriotic epithelial cell spheroids can perform mesothelial clearance similar to ovarian cancer spheroids, though normal endometrial cells do not clear as well as endometriosis cells. Additionally, we demonstrated that our mesothelial clearance assay can test potential pharmacological therapies for endometriosis prior to clinical trials. These results give insight into the development of endometriosis lesions, but further research is needed to determine the mechanisms behind mesothelial clearance in endometriosis. Full article