Rui Medeiros

Endothelial Dysfunction Markers in Ovarian Cancer: VTE Risk and Tumour Prognostic Outcomes

Ovarian cancer (OC) presents daunting lethality rates worldwide, with frequent late-stage diagnosis and chemoresistance, highlighting the need for improved prognostic approaches. Venous thromboembolism (VTE), a major cancer mortality factor, is partially driven by endothelial dysfunction (ED). ED’s pro-inflammatory state fosters tumour progression, suggesting a VTE-independent link between ED and cancer. Given this triad’s interplay, ED markers may influence OC behaviour and patients’ prognosis. Thus, the impact of ED-related genes and single-nucleotide polymorphisms (SNPs) on OC-related VTE and patient thrombogenesis-independent prognosis was investigated. NOS3 upregulation was linked to lower VTE incidence (χ2, p = 0.013), while SELP upregulation was associated with shorter overall survival (log-rank test, p = 0.048). Dismissing patients with VTE before OC diagnosis, SELP rs6136 T allele carriers presented lower progression-free survival (log-rank test, p = 0.038). Nevertheless, due to the SNP minor allele underrepresentation, further investigation is required. Taken together, ED markers seem to exhibit roles that depend on the clinical context, such as tumour-related thrombogenesis or cancer prognosis. Validation with larger cohorts and more in-depth functional studies are needed for data clarification and potential therapeutic strategies exploitation to tackle cancer progression and thrombosis in OC patients.

Paradigm Shift: A Comprehensive Review of Ovarian Cancer Management in an Era of Advancements

Ovarian cancer (OC) is the female genital malignancy with the highest lethality. Patients present a poor prognosis mainly due to the late clinical presentation allied with the common acquisition of chemoresistance and a high rate of tumour recurrence. Effective screening, accurate diagnosis, and personalised multidisciplinary treatments are crucial for improving patients’ survival and quality of life. This comprehensive narrative review aims to describe the current knowledge on the aetiology, prevention, diagnosis, and treatment of OC, highlighting the latest significant advancements and future directions. Traditionally, OC treatment involves the combination of cytoreductive surgery and platinum-based chemotherapy. Although more therapeutical approaches have been developed, the lack of established predictive biomarkers to guide disease management has led to only marginal improvements in progression-free survival (PFS) while patients face an increasing level of toxicity. Fortunately, because of a better overall understanding of ovarian tumourigenesis and advancements in the disease’s (epi)genetic and molecular profiling, a paradigm shift has emerged with the identification of new disease biomarkers and the proposal of targeted therapeutic approaches to postpone disease recurrence and decrease side effects, while increasing patients’ survival. Despite this progress, several challenges in disease management, including disease heterogeneity and drug resistance, still need to be overcome.

Venous Thrombogenesis and Cervical Cancer: Plasma MicroRNAs as Prognostic Indicators of Tumor Behavior

Cervical cancer (CC) is the fourth most common cancer among women globally, with venous thromboembolism (VTE) representing a life-threatening complication. Cancer-associated thrombosis (CAT) arises from tumor-driven activation of hemostasis, worsening prognosis. Recently, circulating microRNAs (miRNAs) have emerged as potential biomarkers for both CAT and cervical tumorigenesis. Thus, this study aimed to assess the implications of five miRNAs—miR-20a-5p, -23a-3p, -125b-5p, -145-5p, and -616-3p—in CC-related VTE context. These miRNAs were quantified by RT-qPCR in plasma from 69 CC patients before treatment. Briefly, VTE occurred in nine patients, decreasing overall survival (OS) [log-rank test, p = 0.005; hazard ratio (HR) = 4.78; 95% confidence interval (CI), 1.42–16.05]. Lower miR-20a-5p levels predicted VTE (ꭓ2 test, p = 0.027) and, in subgroup analyses, they were linked to cervical squamous cell carcinoma (CSCC) and older age (ꭓ2 test, p = 0.003 and p = 0.043, respectively). In VTE patients, miR-145-5p downregulation was associated with improved OS (log-rank test, p = 0.018), an effect also observed in the adenocarcinoma (ADC) subgroup (log-rank test, p = 0.039). The remaining miRNAs showed subtype-specific links to clinicopathological features and survival. These findings highlight the potential value of circulating miRNAs in thrombotic risk and prognosis assessment in CC.

Non-coding RNAs and liquid biopsies: Emerging biomarkers for cervical cancer

Cervical cancer (CC) is the fourth most common malignancy among women worldwide, highlighting the urgent need for improved predictive, diagnostic and prognostic biomarkers to enhance disease management and patient outcomes. Non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and microRNAs (miRNAs), perform various functions in transcriptional, translational and post-translational regulation. Aberrant expression of ncRNAs in CC has been closely associated with disease initiation and progression, underscoring their potential as key regulators of cervical tumorigenesis. Several lncRNAs, such as HOTAIR and PVT1, contribute to cervical tumorigenesis by promoting cell proliferation, migration and invasion. Likewise, circRNAs, such as circ_0018289, act as miRNA sponges, leading to the dysregulation of key target genes. Moreover, specific miRNAs, such as miR-20a and miR-21, promote CC progression (oncogenic miRNAs), whereas others, including miR-214 and miR-218, exhibit a tumor suppressor role. Importantly, many ncRNAs are detectable in body fluids, representing stable and minimally invasive biomarkers suitable for liquid biopsy. Thus, in this comprehensive narrative review, we map the range of candidate ncRNAs reported in the literature and discuss their predictive, diagnostic, prognostic and therapeutic value, including their potential as circulating biomarkers in CC. We also highlight, as a future perspective, how integrated profiling approaches could guide research and support the development of non-invasive strategies for diagnosis, prognostic assessment, and therapy monitoring in CC.

Plasma microRNA Environment Linked to Tissue Factor Pathway and Cancer-Associated Thrombosis: Prognostic Significance in Ovarian Cancer

Ovarian cancer (OC) is a leading cause of death among gynaecological malignancies. The haemostatic system, which controls blood flow and prevents clotting disorders, paradoxically drives OC progression while increasing the risk of venous thromboembolism (VTE). MicroRNAs (miRNAs) have emerged as crucial in understanding VTE pathogenesis. Exploring the connection between cancer and thrombosis through these RNAs could lead to novel biomarkers of cancer-associated thrombosis (CAT) and OC, as well as potential therapeutic targets for tumour management. Thus, this study examined the impact of eight plasma miRNAs targeting the tissue factor (TF) coagulation pathway—miR-18a-5p, -19a-3p, -20a-5p, -23a-3p, -27a-3p, -103a-3p, -126-5p and -616-3p—in 55 OC patients. Briefly, VTE occurrence post-OC diagnosis was linked to shorter disease progression time (log-rank test, p = 0.024) and poorer overall survival (OS) (log-rank test, p < 0.001). High pre-chemotherapy levels of miR-20a-5p (targeting coagulation factor 3 (F3) and tissue factor pathway inhibitor 2 (TFPI2)) and miR-616-3p (targeting TFPI2) predicted VTE after OC diagnosis (χ2, p < 0.05). Regarding patients’ prognosis regardless of VTE, miR-20a-5p independently predicted OC progression (adjusted hazard ratio (aHR) = 6.13, p = 0.005), while miR-616-3p significantly impacted patients’ survival (aHR = 3.72, p = 0.020). Further investigation is warranted for their translation into clinical practice.

Long Non-Coding RNAs: Bridging Cancer-Associated Thrombosis and Clinical Outcome of Ovarian Cancer Patients

Ovarian cancer (OC) and venous thromboembolism (VTE) have a close relationship, in which tumour cells surpass the haemostatic system to drive cancer progression. Long non-coding RNAs (lncRNAs) have been implicated in VTE pathogenesis, yet their roles in cancer-associated thrombosis (CAT) and their prognostic value are unexplored. Understanding how these lncRNAs influence venous thrombogenesis and ovarian tumorigenesis may lead to the identification of valuable biomarkers for VTE and OC management. Thus, this study evaluated the impact of five lncRNAs, namely MALAT1, TUG1, NEAT1, XIST and MEG8, on a cohort of 40 OC patients. Patients who developed VTE after OC diagnosis had worse overall survival compared to their counterparts (log-rank test, p = 0.028). Elevated pre-chemotherapy MEG8 levels in peripheral blood cells (PBCs) predicted VTE after OC diagnosis (Mann–Whitney U test, p = 0.037; Χ2 test, p = 0.033). In opposition, its low levels were linked to a higher risk of OC progression (adjusted hazard ratio (aHR) = 3.00; p = 0.039). Furthermore, low pre-chemotherapy NEAT1 levels in PBCs were associated with a higher risk of death (aHR = 6.25; p = 0.008). As for the remaining lncRNAs, no significant association with VTE incidence, OC progression or related mortality was observed. Future investigation with external validation in larger cohorts is needed to dissect the implications of the evaluated lncRNAs in OC patients.

Haemostatic gene variations in cervical cancer-associated venous thrombosis: considerations for clinical strategies

Venous thromboembolism (VTE) is a life-threatening haemostatic disease frequently diagnosed among the cancer population. The Khorana Score is currently the primal risk assessment model to stratify oncological patients according to their susceptibility to VTE, however, it displays a limited performance. Meanwhile, intensive research on VTE pathophysiology in the general population has uncovered a range of single-nucleotide polymorphisms (SNPs) associated with the condition. Nonetheless, their predictive ability concerning cancer-associated thrombosis (CAT) is controversial. Cervical cancer (CC) patients undergoing chemoradiotherapy often experience VTE, which negatively affects their survival. Thus, aiming for an improvement in thromboprophylaxis, new thrombotic biomarkers, including SNPs, are currently under investigation. In this study, the predictive capability of haemostatic gene SNPs on CC-related VTE and their prognostic value regardless of VTE were explored. Six SNPs in haemostatic genes were evaluated. A total of 401 CC patients undergoing chemoradiotherapy were enrolled in a retrospective cohort study. The implications for the time to VTE occurrence and overall survival (OS) were assessed. CAT considerably impacted the CC patients' OS (log-rank test, P  C) showed a significant association with the risk of CC-related VTE (CC/CT vs. TT, log-rank test, P = 0.002; C allele, Cox model, hazard ratio (HR) = 6.99 and P = 0.009), while F2 rs1799963 (G > A) demonstrated an important prognostic value regardless of VTE (AA/AG vs. GG, log-rank test, P = 0.020; A allele, Cox model, HR = 2.76 and P = 0.026). For the remaining SNPs, no significant associations were detected. The polymorphisms SERPINE1 rs2070682 and F2 rs1799963 could be valuable tools in clinical decision-making, aiding in thromboprophylaxis and CC management, respectively.

Implications of venous thromboembolism GWAS reported genetic makeup in the clinical outcome of ovarian cancer patients

Ovarian cancer (OC) represents the most lethal gynaecological neoplasia. Conversely, venous thromboembolism (VTE) and OC are intricately connected, with many haemostatic components favouring OC progression. In light of this bilateral relationship, genome-wide association studies (GWAS) have reported several single-nucleotide polymorphisms (SNPs) associated with VTE risk that could be used as predictors of OC clinical outcome for better therapeutic management strategies. Thus, the present study aimed to analyse the impact of VTE GWAS-identified SNPs on the clinical outcome of 336 epithelial ovarian cancer (EOC) patients. Polymorphism genotyping was performed using the TaqMan

MiR-150 and miR-155 expression predicts survival of cervical cancer patients: a translational approach to novel prognostic biomarkers

High-risk human papillomavirus (HPV) is the aetiological agent of cervical cancer, which remains the fourth leading cause of cancer death in women worldwide. K14-HPV16 transgenic mice are a model for HPV-induced cancers, which undergo multistep squamous carcinogenesis at the skin, that is histologically and molecularly similar to carcinogenesis of the human cervix. Previous screens of differentially regulated microRNAs (miRs) using K14-HPV16 mice showed a role for miR-21, miR-155, miR-150, miR-146a, miR-125b and miR-223 during carcinogenesis. We now aim to translate these observations into the clinical setting, using data provided by The Cancer Genome Atlas (TCGA) to explore whether those microRNAs can influence the survival of cervical cancer patients. Results showed that low miR-150, miR-155 and miR-146a expression levels in primary tumours were associated with poor overall survival. However, only miR-150 and miR-155 were found to be independent predictors, increasing the risk of death. When patients were stratified by clinical stage, low miR-150, miR-155, miR-146a and miR-125b were associated with poor survival for clinical stages I and II. Only low miR-150 expression increased the death risk. We conclude that miR-150 and miR-155 may be potentially applied as prognostic biomarkers in cervical cancer patients. However, further investigation is required to determine their applicability.

Impact of cervicovaginal microbiome on the risk of cervical abnormalities development

AbstractThe vaginal microbiome has emerged as potentially influencing the natural history of Human Papillomavirus (HPV) infections and their clinical impact. We aimed to characterize the vaginal microbiome in samples from 807 high‐risk HPVs (Hr‐HPV) positive women with a mean age of 41.45 ± 10.79 years who participated in the Regional Cervical Cancer Screening Program from the Northern Region of Portugal. Microbiome analysis was performed with commercial kits for the detection of 21 microorganisms. The most frequent microorganisms were Ureaplasma parvum (52.5%), Gardnerella vaginalis (GV) (34.5%), Atopobium vaginae (AV) (32.6%), Lacto (30.7%), and Mycoplasma hominis (MH) (23.5%). The distribution according to age reveals that MH, Mega1, GV, BVab2, AV, and Mob were more prevalent in women older than 41 years of age (p < 0.050), while Lacto is significantly decreased in this group (23.5% vs. 39.4%, p < 0.001; RR = 0.47). The risk analysis showed that Hr‐HPV‐16/‐18 and Hr‐HPV‐9val genotypes are associated with an increased risk of developing cervical abnormalities, while Lacto (p < 0.001; odd ratio [OR] = 0.33), GV (p = 0.0111; OR = 0.41), AV (p = 0.033; OR = 0.53) and Mob (p = 0.022; OR = 0.29) are associated with protection. Similar results were found for the risk of development atypical squamous cells cannot exclude HSIL/high‐grade squamous intraepithelial lesion. Overall, the multivariate analysis confirmed that lactobacillus and bacteria associated with bacterial vaginosis (GV, AV, and Mob) are associated with protection against the development of cervical abnormalities. This study provides important data to be included in the future management of risk stratification for Hr‐HPV‐positive women.