Chimeric Antigen Receptor Design and Efficacy in Ovarian Cancer Treatment.

Our increased understanding of tumour biology gained over the last few years has led to the development of targeted molecular therapies, e.g., vascular endothelial growth factor A (VEGF-A) antagonists, poly[ADP-ribose] polymerase 1 (PARP1) inhibitors in hereditary breast and ovarian cancer syndrome (BRCA1 and BRCA2 mutants), increasing survival and improving the quality of life. However, the majority of ovarian cancer (OC) patients still do not have access to targeted molecular therapies that would be capable of controlling their disease, especially resistant or relapsed. Chimeric antigen receptors (CARs) are recombinant receptor constructs located on T lymphocytes or other immune cells that change its specificity and functions. Therefore, in a search for a successful solid tumour therapy using CARs the specific cell surface antigens identification is crucial. Numerous in vitro and in vivo studies, as well as studies on humans, prove that targeting overexpressed molecules, such as mucin 16 (MUC16), annexin 2 (ANXA2), receptor tyrosine-protein kinase erbB-2 (HER2/neu) causes high tumour cells toxicity and decreased tumour burden. CARs are well tolerated, side effects are minimal and they inhibit disease progression. However, as OC is heterogenic in its nature with high mutation diversity and overexpression of different receptors, there is a need to consider an individual approach to treat this type of cancer. In this publication, we would like to present the history and status of therapies involving the CAR T cells in treatment of OC tumours, suggest potential T cell-intrinsic determinants of response and resistance as well as present extrinsic factors impacting the success of this approach.

Serum Concentrations of Carotenoids and Fat-Soluble Vitamins in Relation to Nutritional Status of Patients with Ovarian Cancer.

In this study, we aimed to determine serum concentrations of carotenoids and fat-soluble vitamins (FSVs) in ovarian cancer (OC) patients categorized by clinical and nutritional status and to compare obtained results with healthy controls. We used single-step extraction methods throughout the study. Serum concentrations of the bioactive compounds were measured using HPLC. The evaluation of the nutritional status of patients was performed with scored PG-SGA questionnaire.The serum bioactive compound levels were significantly lower in early-stage OC patients (FIGO I/II) when compared to healthy controls for all-trans-retinoic acid, 25-hydroxycholecalciferol, all-trans-retinol, astaxanthin, zeaxanthin, lycopene and α-carotene, respectively. In patients with advanced-stage of OC (FIGO III/IV) the mean serum concentrations of carotenoids and FSVs were significantly lower than in healthy controls, excluding lutein and ß + γ-tocopherol levels. Patients with OC and concomitant moderate or severe malnourishment showed significantly lower levels of 25-hydroxycholecalciferol and all-trans-retinol. It seems that our extraction and measurement methods for the bioactive compounds could be used in both, clinical and nutritional studies. The obtained results confirm that the PG-SGA assessment might be considered not only as a malnutrition assessment tool, but also for planning early nutritional intervention in patients with OC.

Clinical value of selected markers of angiogenesis, inflammation, insulin resistance and obesity in type 1 endometrial cancer.

BACKGROUND: It is a well-known fact show that the risk of developing endometrial cancer (type 1 EC) is strongly associated with obesity. In this study, selected markers, such as obesity, insulin resistance, angiogenesis and inflammation markers related to EC type 1 progression and patients' survival data were analyzed. METHODS: To measure levels of adiponectin, C-reactive protein (CRP), vascular endothelial growth factor-A (VEGF-A), angiopoietin-2 (Ang-2), insulin-like growth factor-1 (IGF-1), insulin and C-peptide in 176 preoperative serum samples, the immunoassay technique (EMIT) has been applied. RESULTS: Angiopoietin-2 levels increase with age (P = 0.005), FIGO stage (p = 0.042), myometrial invasion (P = 0.009) and LVSI (P < 0.001). The CRP levels increase with age (P = 0.01), as well as the advancement of the FIGO stage (P < 0.001), higher tumor grade (P = 0.012), and myometrial invasion (P < 0.001). A positive correlation between serum Ang-2 and CRP levels was demonstrated (r = 0.44; p < 0.001). Kaplan-Meier survival analysis showed that patients with high CRP levels in serum and Ang-2 presented a worse outcome (P = 0.03 and P = 0.015, respectively). Cox regression analysis of individual predictors revealed that high serum levels of Ang-2, CRP, advanced clinical FIGO stage (P < 0.001, respectively), old age (P = 0.013) were all significant overall survival predictors. By means of multivariate analysis, their predictive significance was confirmed. CONCLUSION: Our study provides evidence that serum levels of Ang-2 and CRP may serve as predictors for assessment of the clinical stage of type 1 EC and are significantly associated with poor prognosis. It is likely that angiogenesis and inflammation associated with obesity have a significant impact on EC type 1 progression and survival rate of patients.

Preoperative HE4, CA125 and ROMA in the differential diagnosis of benign and malignant adnexal masses.

BACKGROUND: The aim of this study was to evaluate HE4, CA125 and ROMA in the preoperative differentiation benign ovarian diseases from epithelial ovarian cancer depending on the menopausal status. METHODS: In order to estimate markers' concentrations in the serum of women with benign ovarian disease (n = 128) and with epithelial ovarian carcinoma (n = 96) the electrochemiluminescence (ECLIA) technique has been applied. RESULTS: Using the ROC analysis, although no statistical differences were found among their AUCs, the ROMA algorithm seems to be effective in gathering the diverse performance of HE4 and CA125. The AUC for HE4, CA125 and ROMA for all patients were: 0.895; 0.879 and 0.918, respectively. At established new optimal cutoff values for HE4, CA125 and ROMA we found higher specificity in postmenopausal compared to premenopausal women (96.9 vs 89.8 % and 97.7 vs 84.1 % and 95.9 vs 89.1 %, respectively). The sensitivity of HE4 in pre- and postmenopausal women was similar (83.5 vs 83.8 %), while for CA125 was the highest in premenopausal women (87.0 vs 84.1 %). For HE4, CA125 and ROMA the negative predictive value was high (97.6, 93.9 and 94.4 %, respectively). CONCLUSIONS: The ROMA algorithm shows the best diagnostic performance to distinguish epithelial ovarian cancer from benign ovarian disease. We found the high specificity of HE4 and CA125 while differentiating ovarian benign diseases from epithelial ovarian cancer in postmenopausal women and the high sensitivity of CA125 in detecting epithelial ovarian cancer in premenopausal patients.

Comparison of Various Databases for Estimation of Dietary Polyphenol Intake in the Population of Polish Adults.

The primary aim of the study was to estimate the consumption of polyphenols in a population of 6661 subjects aged between 20 and 74 years representing a cross-section of the Polish society, and the second objective was to compare the intakes of flavonoids calculated on the basis of the two commonly used databases. Daily food consumption data were collected in 2003-2005 using a single 24-hour dietary recall. Intake of total polyphenols was estimated using an online Phenol-Explorer database, and flavonoid intake was determined using following data sources: the United States Department of Agriculture (USDA) database combined of flavonoid and isoflavone databases, and the Phenol-Explorer database. Total polyphenol intake, which was calculated with the Phenol-Explorer database, was 989 mg/day with the major contributions of phenolic acids 556 mg/day and flavonoids 403.5 mg/day. The flavonoid intake calculated on the basis of the USDA databases was 525 mg/day. This study found that tea is the primary source of polyphenols and flavonoids for the studied population, including mainly flavanols, while coffee is the most important contributor of phenolic acids, mostly hydroxycinnamic acids. Our study also demonstrated that flavonoid intakes estimated according to various databases may substantially differ. Further work should be undertaken to expand polyphenol databases to better reflect their food contents.

Dietary antioxidant capacity of the patients with cardiovascular disease in a cross-sectional study.

BACKGROUND: The purpose of this study was to establish sources and patterns of antioxidant, polyphenol and flavonoid intakes in men and women with cardiovascular disease (CVD). METHODS: The subjects with CVD and healthy controls (HC) were participants of the Polish National Multicenter Health Survey (WOBASZ). Food intakes were measured with the 1-day 24-hour recall method. A self-developed database was used to calculate dietary total antioxidant capacity (DTAC), dietary total polyphenol content (DTPC) and dietary total flavonoid content (DTFC). RESULTS: DTAC did not differ between the men with CVD and HC men (6442 vs. 6066 µmol trolox equivalents - TE), but in the women with CVD it was significantly higher than in the HC women (6182 vs. 5500 µmol TE). The main sources of antioxidants in the males with CVD were: tea, coffee, apples, and nuts and seeds, and tea, coffee and apples in HC. In the females they were: tea, coffee, apples and strawberries, both in the women with CVD and HC. DTPC in the men with CVD did not differ from HC (1198 vs. 1114 mg gallic acid equivalents, GAE). In the females, DTPC was significantly higher in the subjects with CVD as compared to HC (1075 vs. 981 mg GAE). Predominant sources of polyphenols were: tea, coffee, cabbage, potatoes, apples and white bread in the men with CVD, and tea, coffee, potatoes, white bread and apples in HC, while in the women (both with CVD and HC): tea, coffee, apples, potatoes and cabbage. No differences in DTFC have been found between the males with CVD and HC (212 vs. 202 mg quercetine equivalents, QE). In the women with CVD, DTFC was significantly higher than in HC (200 vs. 177 mg QE). Main sources of flavonoids in all participants (men and women, CVD and HC) were tea, apples, cabbage and coffee. CONCLUSIONS: Polish men and women faced with CVD beneficially modify their dietary practices by enhancing intakes of foods that are sources of antioxidants, polyphenols and flavonoids. Different sources and patterns of antioxidant, polyphenol and flavonoid intakes, however, between male and female patients with CVD were observed.

Potential application of curcumin and its analogues in the treatment strategy of patients with primary epithelial ovarian cancer.

Recent findings on the molecular basis of ovarian cancer development and progression create new opportunities to develop anticancer medications that would affect specific metabolic pathways and decrease side systemic toxicity of conventional treatment. Among new possibilities for cancer chemoprevention, much attention is paid to curcumin-A broad-spectrum anticancer polyphenolic derivative extracted from the rhizome of Curcuma longa L. According to ClinicalTrials.gov at present there are no running pilot studies, which could assess possible therapeutic benefits from curcumin supplementation to patients with primary epithelial ovarian cancer. Therefore, the goal of this review was to evaluate potential preclinical properties of curcumin and its new analogues on the basis of in vivo and in vitro ovarian cancer studies. Curcumin and its different formulations have been shown to display multifunctional mechanisms of anticancer activity, not only in platinum-resistant primary epithelial ovarian cancer, but also in multidrug resistant cancer cells/xenografts models. Curcumin administered together with platinum-taxane chemotherapeutics have been reported to demonstrate synergistic effects, sensitize resistant cells to drugs, and decrease their biologically effective doses. An accumulating body of evidence suggests that curcumin, due to its long-term safety and an excellent profile of side effects should be considered as a beneficial support in ovarian cancer treatment strategies, especially in patients with platinum-resistant primary epithelial recurrent ovarian cancer or multidrug resistant disease. Although the prospect of curcumin and its formulations as anticancer agents in ovarian cancer treatment strategy appears to be challenging, and at the same time promising, there is a further need to evaluate its effectiveness in clinical studies.