Endometrial cancer (EC) is the most frequent gynecological malignancy in developed countries and requires a relatively invasive diagnostic evaluation and operative therapy as the primary therapeutic approach. Angiogenesis is one of the main processes needed for cancer growth and spread. The production of angiogenic factors (AFs) appears early in the process of carcinogenesis. The detection of AFs in plasma and tissue and a better understanding of the angiogenic properties of EC may contribute not only to earlier but also more specific diagnosis and consequently tailored and individual therapeutic approaches. AFs and their receptors also have high potential as binding sites for targeted cancer therapy. In this review, we discuss angiogenesis in EC and the characteristics of the AFs that most contribute to angiogenesis in EC. We also highlight therapeutic strategies that target angiogenesis as potential EC therapy.
Preoperative determination of the extent of endometrial cancer (EC) would avoid the complications associated with radical surgery. Screening of patients’ plasma biomarkers might enable a more precise diagnosis of EC and a tailored treatment approach. This prospective case-control monocentric pilot study included 76 postmenopausal women (38 endometrioid EC patients and 38 control patients with benign gynecological conditions), and 37 angiogenic factors (AFs) were investigated as potential biomarkers for EC. AF concentrations in preoperative plasma samples were measured using Luminex xMAP™ multiplexing technology. The plasma levels of sTie-2 and G-CSF were significantly lower in EC compared to control patients, whereas the plasma levels of leptin were significantly higher in EC patients. Neuropilin-1 plasma levels were significantly higher in patients with type 2 EC (grade 3) compared to patients with lower grade cancer or controls. Follistatin levels were significantly higher in patients with lymphovascular invasion, and IL-8 plasma levels were significantly higher in patients with metastases. If validated, the plasma concentrations of the indicated AFs could represent an important additional diagnostic tool for the early detection and characterization of EC. This could guide the decision-making on the extent of surgery. Further studies with larger patient numbers are currently ongoing.
BackgroundThe diversity of endometrial cancer (EC) dictates the need for precise early diagnosis and pre-operative stratification to select treatment options appropriately. Non-invasive biomarkers invaluably assist clinicians in managing patients in daily clinical practice. Currently, there are no validated diagnostic or prognostic biomarkers for EC that could accurately predict the presence and extent of the disease.MethodsOur study analyzed 202 patients, of whom 91 were diagnosed with EC and 111 were control patients with the benign gynecological disease. Using Luminex xMAP™ multiplexing technology, we measured the pre-operative plasma concentrations of six previously selected angiogenic factors – leptin, IL-8, sTie-2, follistatin, neuropilin-1, and G-CSF. Besides basic statistical methods, we used a machine-learning algorithm to create a robust diagnostic model based on the plasma concentration of tested angiogenic factors.ResultsThe plasma levels of leptin were significantly higher in EC patients than in control patients. Leptin was higher in type 1 EC patients versus control patients, and IL-8 was higher in type 2 EC versus control patients, particularly in poorly differentiated endometrioid EC grade 3. IL-8 plasma levels were significantly higher in EC patients with lymphovascular or myometrial invasion. Among univariate models, the model based on leptin reached the best results on both training and test datasets. A combination of age, IL-8, leptin and G-CSF was determined as the most important feature for the multivariate model, with ROC AUC 0.94 on training and 0.81 on the test dataset. The model utilizing a combination of all six AFs, BMI and age reached a ROC AUC of 0.89 on both the training and test dataset, strongly indicating the capability for predicting the risk of EC even on unseen data.ConclusionAccording to our results, measuring plasma concentrations of angiogenic factors could, provided they are confirmed in a multicentre validation study, represent an important supplementary diagnostic tool for early detection and prognostic characterization of EC, which could guide the decision-making regarding the extent of treatment.
Methodology We performed a randomized controlled study. Patients with HSIL aged 18-40 years were included and treated with either imiquimod, 3 times per week for 16 weeks (experimental arm), or with LLETZ (control arm). Treatment success was evaluated by regression to low-grade SIL (LSIL) 20 weeks after initiation of the treatment in the experimental arm and by negative cytology 6 months after LLETZ in the control arm. Secondary outcome was occurrence of the side effects during and after treatment. Statistical analysis was performed using SPSS Statistics Programme. Statistical significance was set at p-value<0.05. Results We included 104 patients. In the experimental arm, 43 out of 52 patients (82.7%) completed treatment, while in the control arm, all of the 52 patients received the planned treatment (100%). Treatment with imiquimod was successful in 62.8% and treatment with LLETZ in 75.0%, the difference was not statistically significant (p-value=0.288). When evaluating treatment success in the intermediate risk subgroup (patients with cervical intraepithelial neoplasia grade 2 -CIN 2), there were also no statistically significant differences between groups (p-value=0.366). However, LLETZ was significantly more successful in patients with CIN 3 lesions (p-value=0.012). We did not observe any cases of progression of the precancerous disease to cancer. Side effects and severe side effects were significantly more prevalent in the imiquimod than in the LLETZ group (88.5% vs. 44.2% (p-value<0.001) and 51.9% vs. 13.5% (p-value<0.001), respectively). The most prevalent side effects were vaginal inflammation, flu-like and lower urinary tract symptoms. Over the course of the treatment with imiquimod, overall occurrence and the severity of side effects decreased. Conclusion Topical imiquimod has a potential of becoming an alternative treatment for HSIL, especially in younger women with intermediate risk HSIL. However, its use is associated with higher occurrence of side effects, which can affect patients' quality of life. In the future, larger studies evaluating the long-term effects of this treatment are needed, especially in the view of disease progression and recurrence. Disclosures The authors declare no competing interests. This research was financially supported by UMC Maribor.
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