Search Results (440)

High-grade serous ovarian cancer (HGSOC) is the most lethal form of gynecologic cancer, with limited treatment options and a poor prognosis. Epigenetic factors, such as microRNAs (miRNAs) and DNA methylation, play pivotal roles in cancer progression, yet their specific contributions to HGSOC remain insufficiently understood. In this study, we performed comprehensive high-throughput analyses to identify dysregulated miRNAs in HGSOC and investigate their epigenetic regulation. Analysis of tissue samples from advanced-stage HGSOC patients revealed 20 differentially expressed miRNAs, 11 of which were corroborated via RT-qPCR in patient samples and cancer cell lines. Among these, miR-145-3p was consistently downregulated post-neoadjuvant therapy and was able to distinguish tumoural from control tissues. Further investigation confirmed that DNA methylation controls MIR145 expression. Functional assays showed that overexpression of miR-145-3p significantly reduced cell migration and induced G0/G1 cell cycle arrest by modulating the cyclin D1-CDK4/6 pathway. These findings suggest that miR-145-3p downregulation enhances cell proliferation and motility in HGSOC, implicating its restoration as a potential therapeutic target focused on G1/S phase regulation in the treatment of HGSOC. Full article

Background: Serous tubal intraepithelial carcinoma (STIC) is an early-stage cancerous lesion found in the fallopian tubes, often at the fimbrial end. It is strongly associated with high-grade serous carcinoma (HGSC), a highly aggressive type of ovarian cancer. STIC is considered a precursor to many HGSC cases, originating in the fallopian tubes. Its development is frequently linked to mutations in the TP53 gene, leading to the formation of a p53 signature, an early abnormality that may progress to HGSC. This signature is more common in BRCA mutation carriers, explaining the higher incidence of STIC in this group. The aim of this review is to evaluate the literature on the incidence of serous tubal intraepithelial carcinoma in patients (both BRCA-positive and BRCA-negative) undergoing preventive salpingo-oophorectomy, analysing the available data and identifying associations between specific characteristics and the onset of STIC. Methods: A comprehensive review of the literature from 2016 to 2023 was conducted using PubMed, focusing on studies analysing the incidence of STIC in BRCA-positive patients undergoing preventive salpingo-oophorectomy. Data on patient characteristics, interventions, outcomes, and incidence of STIC were extracted and analysed. Results: Nine international studies were included in the review, reporting varying incidences of STIC among patients undergoing salpingo-oophorectomy. The overall incidence of STIC in all the women included in the studies was 7.31%, while that in the BRCA-mutated women was approximately 6.08%. Notably, the presence of the TP53 signature was significantly associated with the occurrence of STIC. Conclusions: The etiopathogenesis of STIC involves complex interactions between genetic, environmental, and molecular factors. Further research is needed to fully understand its mechanisms and identify additional risk factors beyond BRCA mutations. Establishing a national database of STIC cases could facilitate future research and improve patient outcomes. Full article

Antibody–drug conjugates targeting folate receptor alpha (FRα) are a promising treatment for platinum-resistant ovarian cancer (OC) with high FRα expression. Challenges persist in accurately assessing FRα expression levels. Our study aimed to better elucidate FRα gene expression and identify mRNA signatures in OC. We pooled OC gene expression data from 16 public datasets, encompassing 1832 OC and 30 normal ovarian tissues. Additional data included DNA copy number and methylation data from TCGA and protein data from 363 cancer cell lines from the Broad Institute Cancer Cell Line Encyclopedia. FOLR1 mRNA expression was significantly correlated with protein expression in pan-cancer cell lines and ovarian cancer cell lines. FOLR1 expression was higher in OC samples than in normal ovarian tissues (OR = 3.88, p = 6.97 × 10⁻¹²). Patients with high FOLR1 expression were more likely to be diagnosed with serous histology, FIGO stage III–IV, and high-grade tumors; however, nearly similar percentages of patients with low FOLR1 expression were also diagnosed with these features. FOLR1 mRNA expression was not correlated with platinum sensitivity or complete surgery, nor with prognosis. However, we identified a 187-gene signature associated with high FOLR1 expression that was significantly associated with improved survival (HR = 0.71, p = 1.18 × 10⁻⁶), independently from clinicopathological features. We identified a gene expression signature correlated to high FRα expression and OC prognosis, which may be used to refine therapeutic strategies targeting FRα in OC. These findings warrant validation in larger cohorts. Full article

Background: The aim of this study was to determine the differences in diffusion-weighted imaging (DWI) and dynamic contrast enhancement (DCE) parameters between patients with peritoneal high-grade serous ovarian cancer (HGSOC) recurrence with BRCA mutations (BRCAmut) or BRCA wild type (BRCAwt). Materials and Methods: We retrospectively analyzed the abdominal and pelvic magnetic resonance (MR) images of 43 patients suspected of having recurrent HGSOC, of whom 18 had BRCA1/2 gene mutations. Patients underwent MRI examination via a 1.5 T MRI scanner, and the analyzed parameters were as follows: apparent diffusion coefficient (ADC), time to peak (TTP) and perfusion maximum enhancement (Perf. Max. En.). Results: The mean ADC in patients with BRCAwt was lower than that in patients with BRCAmut: 788.7 (SD: 139.5) vs. 977.3 (SD: 103), p-value = 0.00002. The average TTP value for patients with BRCAwt was greater than that for patients with mutations: 256.3 (SD: 50) vs. 160.6 (SD: 35.5), p-value < 0.01. The Perf. Max. En. value was lower in the BRCAwt group: 148.6 (SD: 12.3) vs. 233.6 (SD: 29.2), p-value < 0.01. Conclusion: Our study revealed a statistically significant correlation between DWI and DCE parameters in examinations of peritoneal metastasis in patients with BRCA1/2 mutations. Adding DCE perfusion to the MRI protocol for ovarian cancer recurrence in patients with BRCAmut may be a valuable tool. Full article

Background/Objectives: Clinical use of poly(ADP-ribose) polymerase inhibitors (PARPis) against metastatic high-grade serous ovarian carcinoma (HGSOC) is limited to cases with deficient a homologous recombination (HR). Our objective was to determine whether the impairment of the fractalkine receptor (CX₃CR1) could sensitize HR-proficient cases to PARPis. Methods: The efficacy of a dual drug combination, including AZD8797, an inhibitor of CX₃CR1, and several PARPis was examined using cell lines and xenograft models. Results: The effectiveness of PARPis and AZD8797 drug combinations ranged from additive to strongly synergistic. Olaparib was synergistic with AZD8797 in OVCAR-4, Caov-3, and OHSAHO. Niraparib and AZD8797 produced synergy in OVCAR-4 and ES2. Rucaparib and AZD8797 were strongly synergistic in Caov-3 and OVSAHO. Veliparib was strongly synergistic with AZD8797 in OVCAR-4 and Caov-3. Notably, a combination of veliparib and AZD8797 produced a strong synergistic effect in a xenograft model. Conclusions: While the exact mechanisms determining the nature of the PARPis and AZD8797 interaction remain to be uncovered, our data indicate that, in a subset of models, selected PARPis strongly synergize with the inhibition of CX₃CR1, suggesting a potential therapeutic opportunity. Full article

Background: There are currently no effective screening measures to detect early or occult tubo-ovarian cancers, resulting in late-stage detection and high mortality. This work explores whether an optical imaging catheter can detect early-stage tubo-ovarian cancers or precursor lesions where they originate in the fallopian tubes. Methods: This device collects co-registered optical coherence tomography (OCT) and autofluorescence imaging (AFI). OCT provides three-dimensional assessment of underlying tissue structures; autofluorescence imaging provides functional contrast of endogenous fluorophores. Ex vivo fallopian tubes (n = 28; n = 7 cancer patients) are imaged; we present methods for the calculation of and analyze eleven imaging biomarkers related to fluorescence, optical attenuation, and OCT texture for their potential to detect tubo-ovarian cancers and other lesions of interest. Results: We visualize folded plicae, vessel-like structures, tissue layering, hemosiderin deposits, and regions of fibrotic change. High-grade serous ovarian carcinoma appears as reduced autofluorescence paired with homogenous OCT and reduced mean optical attenuation. Specimens containing cancerous lesions demonstrate a significant increase in median autofluorescence intensity and decrease in Shannon entropy compared to specimens with no lesion. Non-cancerous specimens demonstrate an increase in optical attenuation in the fimbriae when compared to the isthmus or the ampulla. Conclusions: We conclude that this approach shows promise and merits further investigation of its diagnostic potential. Full article

Background/Objectives: Serous ovarian carcinoma (SOC) is the most common subtype of epithelial ovarian cancer, with high-grade (HGSOC) and low-grade (LGSOC) subtypes presenting distinct clinical behaviours. This study aimed to evaluate histopathologic features in SOC, correlating these with prognostic outcomes, and explore the potential clinical implications. Methods: We analysed 51 SOC cases for lymphovascular space invasion (LVSI), tumour border configuration (TBC), microvessel density (MVD), tumour budding (TB), the tumour–stroma ratio (TSR), the stromal type, tumour-infiltrating lymphocytes (TILs), and tertiary lymphoid structures (TLSs). A validation cohort of 54 SOC cases from The Cancer Genome Atlas (TCGA) was used for comparison. Results: In the discovery set, significant predictors of aggressive behaviour included LVSI, high MVD, high TB, and low TILs. These findings were validated in the validation set where the absence of TLSs, lower peritumoural TILs, immature stromal type, and low TSR were associated with worse survival outcomes. The stromal type was identified as an independent prognostic predictor in SOC across both datasets. Inter-observer variability analysis demonstrated substantial to almost perfect agreement for these features, ensuring the reproducibility of the findings. Conclusions: The histopathological evaluation of immune and stromal features, such as TILs, TLSs, TB, TSR, and stromal type, provides critical prognostic information for SOC. Incorporating these markers into routine pathological assessments could enhance risk stratification and guide treatment, offering practical utility, particularly in low-resource settings when molecular testing is not feasible. Full article

Background/Objectives: Immunohistochemical expression of TRPS1 (trichorhinophalangeal syndrome type 1) protein is usually used by pathologists to confirm breast origin for triple-negative breast cancers (TNBC) or metastatic carcinomas of unknown primary. However, recent studies have reported TRPS1 expression in a variety of non-breast lesions. This review aims to provide a comprehensive evaluation of TRPS1 expression across various tumor types, highlighting both its diagnostic utility and potential pitfalls that may arise in clinical practice. Methods: A thorough search of the PubMed database on TRPS1 immunoexpression in tumor pathology was conducted. While the gene itself has been known for several decades, most studies regarding its use in immunohistochemistry emerged in the late 2010s. Particular emphasis was placed on case reports and cohort studies that examined the implications of TRPS1 expression in non-breast tissues, as well as variations in the results between commercially available TRPS1 clones, which may influence the staining intensity and specificity. Results: TRPS1 demonstrated a strong diagnostic utility in identifying primary breast lesions, particularly in TNBC cases. However, its expression in a growing number of non-breast cancers, such as lung adenocarcinoma, prostate adenocarcinoma, urothelial carcinoma, ovarian high-grade serous carcinoma, and endometrial adenocarcinoma, as well as up to 96% of synovial sarcomas with SS18-SSX fusion, emphasizes the need for caution when interpreting TRPS1 positivity and suggests a multi-marker approach in order to increase the diagnostic accuracy. Conclusions: While TRPS1 remains a highly sensible immunohistochemical marker for confirming breast primary lesions, pathologists should be aware of its low specificity and incorporate complementary diagnostic methods in order to ensure accurate clinical management. Further research should focus on elucidating the molecular pathways regulating TRPS1 expression in various tumor types, which may better define its clinical utility. Full article

Background: Changes in DNA methylation patterns are a pivotal mechanism of carcinogenesis. In some tumors, aberrant methylation precedes genetic changes, while gene expression may be more frequently modified due to methylation alterations than by mutations. Methods: Herein, 128 serous ovarian tumors were analyzed, including borderline ovarian tumors (BOTS) with (BOT.V600E) and without (BOT) the BRAF V600E mutation, low-grade (lg), and high-grade (hg) ovarian cancers (OvCa). The methylome of the samples was profiled with Infinium MethylationEPIC microarrays. Results: The biggest number of differentially methylated (DM) CpGs and regions (DMRs) was found between lgOvCa and hgOvCa. By contrast, the BOT.V600E tumors had the lowest number of DM CpGs and DMRs compared to all other groups and, in relation to BOT, their genome was strongly downmethylated. Remarkably, the ten most significant DMRs, discriminating BOT from lgOvCa, encompassed the MHC region on chromosome 6. We also identified hundreds of DMRs, being of potential use as predictive biomarkers in BOTS and hgOvCa. DMRs with the best discriminative capabilities overlapped the following genes: BAIAP3, IL34, WNT10A, NEU1, SLC44A4, and HMOX1, TCN2, PES1, RP1-56J10.8, ABR, NCAM1, RP11-629G13.1, AC006372.4, NPTXR in BOTS and hgOvCa, respectively. Conclusions: The global genome-wide hypomethylation positively correlates with the increasing aggressiveness of ovarian tumors. We also assume that the immune system may play a pivotal role in the transition from BOTS to lgOvCa. Given that the BOT.V600E tumors had the lowest number of DM CpGs and DMRs compared to all other groups, when methylome is considered, such tumors might be placed in-between BOT and OvCa. Full article

Background: Most patients with ovarian cancer relapse within 2 years. Prospective randomized trials, such as DESKTOP III and SOC-I, have shown the role of secondary cytoreduction in improving oncological outcomes in selected patients, when complete tumor resection is achieved. Recent retrospective series suggest that minimally invasive surgery is a feasible option in oligometastatic recurrences, such as rectal ones. Methods: Five patients with an isolated rectal recurrence infiltrating the bowel wall underwent a robotic rectosigmoid resection with totally intracorporeal colorectal anastomosis. The procedure began with retroperitoneal access to manage the vascular structures, followed by visceral resection with a minimally invasive approach. The standard steps of an en-bloc pelvic resection, including intracorporeal end-to-end anastomosis, were performed. The treatment data were evaluated. Results: The mean age of the patients was 54 years, and their mean body mass index was 30. All patients had at least one previous abdominal surgery and 60% had high-grade serous ovarian cancer at their initial diagnosis. Their mean platinum-free interval was 17.4 months. Complete secondary cytoreduction was achieved in all cases, with histopathology confirming bowel infiltration. The mean procedure duration was 294 min, with an estimated blood loss of 180 mL. No intraoperative complications occurred. The mean hospital stay was 8 days. One patient had a grade 2 postoperative complication. The mean follow-up period was 14 months, with only one patient experiencing a recurrence at the level of the abdominal wall. Conclusions: Robotic rectosigmoid resection is a viable option for complete cytoreduction in isolated recurrent ovarian cancer. Full article

In this work, the HR MAS NMR (high-resolution magic-angle spinning nuclear magnetic resonance) spectroscopy technique was combined with standard histological examinations to investigate the metabolic features of high-grade serous ovarian cancer (HGSOC) with a special focus on the relation between a metabolic profile and a cancer cell fraction. The studied group consisted of 44 patients with HGSOC and 18 patients with benign ovarian tumors. Normal ovarian tissue was also excised from 13 control patients. The metabolic profiles of 138 tissue specimens were acquired on a Bruker Avance III 400 MHz spectrometer. The NMR spectra of the HGSOC samples could be discriminated from those acquired from the non-transformed tissue and were shown to depend on tumor purity. The most important features that differentiate the samples with a high fraction of cancer cells from the samples containing mainly fibrotic stroma are the increased intensities in the spectral regions corresponding to phosphocholine/glycerophosphocholine, phosphoethanolamine/serine, threonine, uridine nucleotides and/or uridine diphosphate (UDP) nucleotide sugars. Higher levels of glutamine, glutamate, acetate, lysine, alanine, leucine and isoleucine were detected in the desmoplastic stroma within the HGSOC lesions compared to the stroma of benign tumors. The HR MAS NMR analysis of the metabolic composition of the epithelial and stromal compartments within HGSOC contributes to a better understanding of the disease’s biology. Full article

Background: High-grade serous carcinoma (HGSC) is the most lethal of gynecological cancers in developed countries. It usually presents late with non-specific symptoms and most cases are diagnosed at an advanced stage, with 5-year overall survival being around 40%. Biomarkers for screening and early diagnosis of this aggressive disease are, thus, a research priority. Extracellular vesicles (EVs) that reflect the cell of origin and that can be isolated from local fluid and plasma by minimally invasive liquid biopsy are such promising biomarkers. Besides EV concentration and molecular profile, which have been the main focus of research for many years, recent studies have also called attention to EV size distribution. The aim of our study was to evaluate the potential of EV concentration and size distribution in local fluid and plasma as diagnostic biomarkers for HGSC. Methods: Paired pretreatment ascites and plasma samples from 37 patients with advanced HGSC and paired pretreatment free peritoneal fluid (FPF) and plasma samples from 40 controls with benign ovarian pathology (BOP) were analyzed using nanoparticle tracking analysis (NTA). Results: We observed a significant difference in EV concentration in local fluid, but not in plasma, between HGSC patients and the control group. We also found a significant difference in EV size distribution in both local fluid and plasma between HGSC patients and the control group. The receiver operating characteristics (ROC) curve analysis of EV characteristics showed excellent diagnostic performance for the mode, D10, and D50 in local fluid and acceptable diagnostic performance for EV concentration and mean EV size in local fluid, as well as for the mode and D10 value in plasma. Conclusions: The results of our study show that EV concentration in local fluid and more importantly EV size distribution in both local fluid and plasma are significantly changed in the presence of HGSC. Future research of size-dependent molecular profiling of EVs could help identify novel diagnostic biomarkers for HGSC. Full article

Macrophages in the tumor microenvironment, termed tumor-associated macrophages (TAMs), promote the progression of various cancer types. However, many mechanisms related to tumor–stromal interactions in epithelial ovarian cancer (EOC) progression remain unclear. High-grade serous ovarian carcinoma (HGSOC) is the most malignant EOC subtype. Herein, immunohistochemistry was performed on 65 HGSOC tissue samples, revealing that patients with a higher infiltration of CD68⁺, CD163⁺, and CD204⁺ macrophages had a poorer prognosis. We subsequently established an indirect co-culture system between macrophages and EOC cells, including HGSOC cells. The co-cultured macrophages showed increased expression of the TAM markers CD163 and CD204, and the co-cultured EOC cells exhibited enhanced proliferation, migration, and invasion. Cytokine array analysis revealed higher YKL40 secretion in the indirect co-culture system. The addition of YKL40 increased proliferation, migration, and invasion via extracellular signal-regulated kinase (Erk) signaling in EOC cells. The knockdown of integrin β4, one of the YKL40 receptors, suppressed YKL40-induced proliferation, migration, and invasion, as well as Erk phosphorylation in some EOC cells. Database analysis showed that high-level expression of YKL40 and integrin β4 correlated with a poor prognosis in patients with serous ovarian carcinoma. Therefore, the YKL40/integrin β4 axis may play a role in ovarian cancer progression. Full article

Epidemiological and observational studies suggest that vitamin D has potential for the chemoprevention of ovarian cancer. The anticancer effect of vitamin D in the fallopian tube epithelium (FTE), which is now thought to harbor the precursor cells for high grade ovarian cancer, is not known. The purpose of this study was to investigate whether vitamin D can inhibit carcinogenesis in the mogp-TAg fallopian tube (FT) ovarian cancer mouse model and examine underlying mechanisms. To test this hypothesis, 3 groups of 40 5-week-old female mogp-TAg mice were divided equally into two cohorts of 20 mice, treated with either vehicle (vitamin D solvent) or the active 1,25(OH)2D3 analogue EB1089, delivered via mini-pump or IP injection or cholecalciferol delivered in the feed. The FTs were characterized histologically and pathologically after 3 and 7 weeks of treatment. The effect of vitamin D on cultured human FTE cells was also examined. After 3 weeks, vitamin D, delivered as either cholecalciferol or EB1089 significantly inhibited FT carcinogenesis. After 7 weeks, cholecalciferol significantly reduced p53 signatures, serous tubal epithelial carcinoma, FT cancer, and plasma CA125 while increasing apoptosis in the FTE. EB1089 had no significant effect on FT carcinogenesis at 7 weeks. Cholecalciferol significantly reduced proliferation and increased apoptosis in vitro in p53-altered FTE cells. In conclusion, vitamin D inhibited FT carcinogenesis by clearing cells with p53 alterations. These data suggest that vitamin D has merit for the chemoprevention of fallopian tube/ovarian cancer. The optimal chemopreventive effect may be dependent on the route of vitamin D administration Full article

Background/Objectives: The present study evaluates predictive implications of the pretherapeutic Fibrinogen–Albumin-Ratio Index (FARI) in high-grade serous ovarian cancer (HGSOC) patients undergoing primary cytoreductive surgery. Methods: This retrospective study included 161 patients with HGSOC International Federation of Gynecology and Obstetrics (FIGO) stage ≥ IIb, who underwent primary cytoreductive surgery followed by platinum-based chemotherapy. Associations between the FARI and complete tumor resection status were described by receiver operating characteristics, and binary logistic regression models were fitted. Results: Higher preoperative FARI values correlated with higher ascites volumes (r = 0.371, p < 0.001), and higher CA125 levels (r = 0.271, p = 0.001). A high FARI cut at its median (≥11.06) was associated with lower rates of complete tumor resection (OR 3.13, 95% CI [1.63–6.05], p = 0.001), and retrained its predictive value in a multivariable model independent of ascites volumes, CA125 levels, FIGO stage, and Charlson Comorbidity Index (CCI). Conclusions: The FARI appears to act as a surrogate for higher intra-abdominal tumor load. After clinical validation, FARI could serve as a readily available serologic biomarker to complement preoperative patient assessment, helping to identify patients who are likely to achieve complete tumor resection during primary cytoreductive surgery. Full article