Polyploidy formation in cancer cells: How a Trojan horse is born.

Ploidy increase has been shown to occur in different type of tumors and participate in tumor initiation and resistance to the treatment. Polyploid giant cancer cells (PGCCs) are cells with multiple nuclei or a single giant nucleus containing multiple complete sets of chromosomes. The mechanism leading to formation of PGCCs may depend on: endoreplication, mitotic slippage, cytokinesis failure, cell fusion or cell cannibalism. Polyploidy formation might be triggered in response to various genotoxic stresses including: chemotherapeutics, radiation, hypoxia, oxidative stress or environmental factors like: air pollution, UV light or hyperthermia. A fundamental feature of polyploid cancer cells is the generation of progeny during the reversal of the polyploid state (depolyploidization) that may show high aggressiveness resulting in the formation of resistant disease and tumor recurrence. Therefore, we propose that modern anti-cancer therapies should be designed taking under consideration polyploidization/ depolyploidization processes, which confer the polyploidization a hidden potential similar to a Trojan horse delayed aggressiveness. Various mechanisms and stress factors leading to polyploidy formation in cancer cells are discussed in this review.

Hypoxia, but Not Normoxia, Reduces Effects of Resveratrol on Cisplatin Treatment in A2780 Ovarian Cancer Cells: A Challenge for Resveratrol Use in Anticancer Adjuvant Cisplatin Therapy.

Natural compounds, such as resveratrol (Res), are currently used as adjuvants for anticancer therapies. To evaluate the effectiveness of Res for the treatment of ovarian cancer (OC), we screened the response of various OC cell lines to the combined treatment with cisplatin (CisPt) and Res. We identified A2780 cells as the most synergistically responding, thus optimal for further analysis. Because hypoxia is the hallmark of the solid tumor microenvironment, we compared the effects of Res alone and in combination with CisPt in hypoxia (pO2 = 1%) vs. normoxia (pO2 = 19%). Hypoxia caused an increase (43.2 vs. 5.0%) in apoptosis and necrosis (14.2 vs. 2.5%), reactive oxygen species production, pro-angiogenic HIF-1α (hypoxia-inducible factor-1α) and VEGF (vascular endothelial growth factor), cell migration, and downregulated the expression of ZO1 (zonula occludens-1) protein in comparison to normoxia. Res was not cytotoxic under hypoxia in contrast to normoxia. In normoxia, Res alone or CisPt+Res caused apoptosis via caspase-3 cleavage and BAX, while in hypoxia, it reduced the accumulation of A2780 cells in the G2/M phase. CisPt+Res increased levels of vimentin under normoxia and upregulated SNAI1 expression under hypoxia. Thus, various effects of Res or CisPt+Res on A2780 cells observed in normoxia are eliminated or diminished in hypoxia. These findings indicate the limitations in using Res as an adjuvant with CisPt therapy in OC.

Bio-Herbicidal Potential of Nanoemulsions with Peppermint Oil on Barnyard Grass and Maize.

Bio-based nanoemulsions are part of green pest management for sustainable agriculture. This study assessed the physicochemical properties and the herbicidal activities of the peppermint essential oil nanoemulsions (PNs) in concentrations 1.0-10% stabilized by Eco-Polysorbate 80 on germinating seeds and young plants of maize and barnyard grass. Based on the design of experiment (DOE) results, the final nanoemulsion formulations were obtained with 1, 1.5, 2, and 5% of essential oil concentration. Biological analyses were conducted to select the most promising sample for selective control of barnyard grass in maize. Seedlings growing in the presence of PNs displayed an overall inhibition of metabolism, as expressed by the calorimetric analyses, which could result from significant differences in both content and composition of carbohydrates. Concentration-response sub estimation showed that leaf-sprayed concentration of PN causing 10% of maize damage is equal to 2.2%, whereas doses causing 50% and 90% of barnyard grass damage are 1.1% and 1.7%, respectively. Plants sprayed with PN at 5% or 10% concentration caused significant drops in relative water content in leaves and Chlorophyll a fluorescence 72 h after spraying. In summary, peppermint nanoemulsion with Eco-Polysorbate 80 at 2% concentration is a perspective preparation for selective control of barnyard grass in maize. It should be analyzed further in controlled and field conditions.

Microencapsulated Caraway Essential Oil Affects Initial Growth of Maize Cultivars.

Caraway (Carum carvi L.) essential oil is a candidate for botanical herbicides. A hypothesis was formulated that the sand-applied maltodextrin-coated caraway oil (MCEO) does not affect the growth of maize (Zea mays L.). In the pot experiment, pre-emergence application of five doses of MCEO was tested on four maize cultivars up to the three-leaf growth stage. The morphological analyses were supported by the measurements of relative chlorophyll content (SPAD), two parameters of chlorophyll a fluorescence, e.g., Fv/Fm and Fv/F0, and fluorescence emission spectra. The analyzed MCEO contained 6.5% caraway EO with carvone and limonene as the main compounds, constituting 95% of the oil. The MCEO caused 7-day delays in maize emergence from the dose of 0.9 g per pot (equal to 96 g m-2). Maize development at the three-leaf growth stage, i.e., length of roots, length of leaves, and biomass of shoots and leaves, was significantly impaired already at the lowest dose of MCEO: 0.4 g per pot, equal to 44 g m-2. A significant drop of both chlorophyll a fluorescence parameters was noted, on average, from the dose of 0.7 g per pot, equal to 69 g m-2. Among the tested cultivars, cv. Rywal and Pomerania were less susceptible to the MCEO compared to the cv. Kurant and Podole. In summary, maize is susceptible to the pre-emergence, sand-applied MCEO from the dose of 44 g m-2.

Transcriptome Remodeling in Gradual Development of Inverse Resistance between Paclitaxel and Cisplatin in Ovarian Cancer Cells.

Resistance to anti-cancer drugs is the main challenge in oncology. In pre-clinical studies, established cancer cell lines are primary tools in deciphering molecular mechanisms of this phenomenon. In this study, we proposed a new, transcriptome-focused approach, utilizing a model of isogenic cancer cell lines with gradually changing resistance. We analyzed trends in gene expression in the aim to find out a scaffold of resistance development process. The ovarian cancer cell line A2780 was treated with stepwise increased concentrations of paclitaxel (PTX) to generate a series of drug resistant sublines. To monitor transcriptome changes we submitted them to mRNA-sequencing, followed by the identification of differentially expressed genes (DEGs), principal component analysis (PCA), and hierarchical clustering. Functional interactions of proteins, encoded by DEGs, were analyzed by building protein-protein interaction (PPI) networks. We obtained human ovarian cancer cell lines with gradually developed resistance to PTX and collateral sensitivity to cisplatin (CDDP) (inverse resistance). In their transcriptomes, we identified two groups of DEGs: (1) With fluctuations in expression in the course of resistance acquiring; and (2) with a consistently changed expression at each stage of resistance development, constituting a scaffold of the process. In the scaffold PPI network, the cell cycle regulator-polo-like kinase 2 (PLK2); proteins belonging to the tumor necrosis factor (TNF) ligand and receptor family, as well as to the ephrin receptor family were found, and moreover, proteins linked to osteo- and chondrogenesis and the nervous system development. Our cellular model of drug resistance allowed for keeping track of trends in gene expression and studying this phenomenon as a process of evolution, reflected by global transcriptome remodeling. This approach enabled us to explore novel candidate genes and surmise that abrogation of the osteomimic phenotype in ovarian cancer cells might occur during the development of inverse resistance between PTX and CDDP.

Agrobiological Interactions of Essential Oils of Two Menthol Mints: Mentha piperita and Mentha arvensis.

This review article discusses the active constituents and potential of two menthol mint oils, Mentha piperita (MPEO) and Mentha arvensis (MAEO), as natural sources for botanical pesticides. The biological activities of these menthol mint oils, which can be useful in agriculture, have been broadly researched, especially toward phytotoxic microorganisms. To a lesser extent, the insecticidal and herbicidal activities of mint EOs have also been studied. It is apparent that the prospect of using menthol mint oils in agriculture is increasing in popularity. A number of investigations showed that the in vitro efficacy of MPEO and MAEO, as well as that of their main constituent, menthol, is pronounced. The results of in vitro research are useful for choosing EOs for further investigations. However, it is clear that in situ experiments are crucial and should be more extensively developed. At the same time, known techniques are to be applied to this area and new methods should be worked out, aiming at the improvement of EOs' pesticidal efficacy and cost-effectiveness, for future implementation in agricultural pest control.

Clinical features and outcomes of germline mutation BRCA1-linked versus sporadic ovarian cancer patients.

BACKGROUND: The role of germline mutations in BRCA1 and BRCA2 genes in the risk of the development of ovarian cancer is clinically well established. BRCA1/2 testing seems to have increasing role in clinical management in patients with advanced ovarian cancer who require treatment with poly(ADP-ribose) polymerase inhibitors. METHODS: Between 2002 - 2008, 125 consecutive patients with ovarian cancer were categorized as having three founder mutations in the BRCA1 gene in Poland as: 5382insC [exon 20], 4153delA [exon 11.17], and 300 T > G [exon 5]. PFS (progression free survival) and OS (overall survival) were determined by Kaplan-Meier analysis with log rank test, univariate comparisons, and multivariate regression analysis using Cox proportional hazards model. RESULTS: Of the 125 patients, the founder mutations of BRCA1 were reported in 17 patients (13.6 %). The median OS was longer for BRCA mutated patients (not reached vs 35.6 months, p = 0.041). PFS was similar for both kinds of ovarian cancer. In multivariate analysis, age ≥70 years, suboptimal surgery, and BRCA1 wild type were poor prognostic factors. The BRCA1 mutation reduced the likelihood of death in ovarian cancer by 86 % (HR 0.14; CI: 0.032-0.650, p = 0.012). CONCLUSION: In conclusion, we found better overall survival for ovarian cancer patients with BRCA1 germline mutations in comparison with patients without these mutations (sporadic) ovarian cancer. Thus, BRCA1 germline mutations appear to be an independent prognostic factor for ovarian cancer.

[Erythropoietin and drug resistance in breast and ovarian cancers]. / Erytropoetyna a lekoopornosc w raku piersi i raku jajnika.

Recombinant human erythropoietin (rhEPO) is used in breast and ovarian cancer patients to alleviate cancer- and chemotherapy-related anemia. Some clinical trials have reported that rhEPO may adversely impact survival and increase the risk of thrombovascular events in patients with breast cancer but not with ovarian cancer. The latter may potentially benefit the most from rhEPO treatment due to the nephrotoxic and myelosuppresive effects of standard platinum-based chemotherapy used in ovarian cancer disease. However, over the last decade the preclinical data have revealed that EPO is not only the principal growth factor and the hormone which regulates erythropoiesis, but also a cytokine with a pleiotropic activity which also can affect cancer cells. EPO can stimulate survival, ability to form metastases and drug resistance not only in continuous breast- and ovarian cancer cell lines but also in breast cancer stem-like cells. EPO receptor (EPOR) can also be constitutively active in both these cancers and, in breast cancer cells, may act in an interaction with estrogen receptor (ER) and epidermal growth factor receptor-2 (HER-2). EPOR, by an EPO-independent mechanism, promotes proliferation of breast cancer cells in cooperation with estrogen receptor, resulting in decreased effectiveness of tamoxifen treatment. In another interaction, as a result of the molecular antagonism between EPOR and HER2, rhEPO protects breast cancer cells against trastuzumab. Both clinical and preclinical evidence strongly suggest the urgent need to reevaluate the traditional use of rhEPO in the oncology setting.

[The role of the Fanconi anemia pathway in the pathophysiology of ovarian cancer]. / Udzial bialek szlaku niedokrwistosci Fanconiego w patofizjologii raka jajnika.

We reviewed the literature on the relationship between the Fanconi anemia pathway (FA) and response to chemotherapy in patients with ovarian cancer. Despite continuous developments in medicine, ovarian cancer remains a challenge for both, physicians and researchers seeking ways to achieve better results of chemotherapy combined with other targeted therapies. Clinically relevant resistance to chemotherapy is a major problem in treating ovarian cancer. Researchers continue to investigate mechanisms responsible for drug resistance in order to develop better therapeutic methods against ovarian cancer. Among the resistance mechanisms, defects in DNA repair, including the FA pathway may be important in increasing the sensitivity of ovarian cancer cells to chemotherapy agents at the clinical level. A growing number of data has shown that disruption of the FA genes may be a useful predictor of OC sensitivity to chemotherapy agents whose activity is based on DNA crosslinking mechanisms.

[Screening for ovarian cancer in BRCA1/BRCA2 mutations carriers]. / Badania przesiewowe w kierunku raka jajnika u nosicielek mutacji genów BRCA1/BRCA2.

Worldwide screening for early detection of ovarian cancer in both, the general population and the group of women at high risk for ovarian cancer including BRCA genes mutations carriers, has proven to be ineffective. The recommended screening methods, including a pelvic examination, transvaginal ultrasound, and CA125 performed biannually continue to fail due to their relatively low sensitivity specificity and positive predictive value tests, as well as the fact that cancer is still detected in advanced stages (FIGO III/IV). However proteomic techniques and the ongoing search for more sensitive and specific biomarkers to increase effectiveness of screening tests for ovarian cancer bring new hope. We reviewed the current literature on screening for ovarian cancer in BRCA genes mutations carriers.

Microwave Control of Reynoutria japonica Houtt., Including Ecotoxicological Aspects and the Resveratrol Content in Rhizomes.

Japanese knotweed (Reynoutria japonica Houtt.) is Poland's invasive weed, for which there is no efficient control method. The rhizomes of this species are rich in resveratrol. In this work, we evaluated (1) the effectiveness of electromagnetic microwaves (MV) in destroying Japanese knotweed using an original device, HOGWEED (MV of 2450 MHz), (2) the ecotoxic effect of the MV on the soil environment, and (3) the resveratrol content in knotweed rhizomes after MV treatment. The field studies were carried out in 2022 in southern Poland. Cut plants were MV-treated for times of 5.0-25.0 min. The MV efficiency was checked 10 and 56 days after treatment (DAT). After MV treatment, fresh soil samples were taken to analyze their ecotoxicity. As a result, at 56 DAT, knotweed was controlled if MV was used for at least 20.0 min. The MV did not affect the soil ecotoxicity. The MV-treated soils were classified as non-toxic or low-toxic. To analyze the resveratrol content, healthy knotweed rhizomes were dug out, treated with MV in the laboratory at 2.5-10.0 min, and analyzed for resveratrol content in HPLC-MS/MS. As a result, the resveratrol in the rhizomes significantly decreased in a time-dependent manner following MV exposure.

The effect of caraway oil-loaded bio-nanoemulsions on the growth and performance of barnyard grass and maize.

A proper formulation is crucial to improve the herbicidal effects of essential oils and their selectivity. In this study, we investigated the physicochemical properties of bio-based nanoemulsions (CNs) containing several concentrations of caraway (Carum carvi) essential oil stabilized with Eco Tween 80, as a surfactant, maintaining 1:1 proportions. Detailed physicochemical characteristics of the CNs revealed that their properties were most desired at 2% of the oil and surfactant, i.e., the smallest droplet size, polydispersity index, and viscosity. The CNs caused biochemical changes in maize and barnyard grass (Echinochloa crus-galli) seedlings, however, to a different extent. Barnyard grass has overall metabolism (measured as a thermal power) decreased by 39-82% when exposed to the CNs. The CNs triggered changes in the content and composition of carbohydrates in the endosperm of both species' seedlings in a dose-response manner. The foliar application of CNs caused significant damage to tissues of young maize and barnyard grass plants. The effective dose of the CN (ED50, causing a 50% damage) was 5% and 17.5% oil in CN for barnyard grass and maize tissues, respectively. Spraying CNs also decreased relative water content in leaves and affected the efficiency of photosynthesis by disturbing the electron transport chain. We found that barnyard grass was significantly more susceptible to the foliar application of CNs than maize, which could be used to selectively control this species in maize crops. However, further studies are needed to verify this hypothesis under field conditions.

Biochemistry of microwave controlled Heracleum sosnowskyi (Manden.) roots with an ecotoxicological aspect.

Sosnowski hogweed is an invasive weed in eastern-middle Europe that is dangerous to human health and the environment. The efficacy of its control using chemical and mechanical methods is limited. Electromagnetic radiation (microwaves) could be an environmentally friendly alternative for controlling this species. This study aims to: (1) Determine the effect of varying microwave treatment (MWT) durations on the control of S. hogweed using a device emitting microwaves at 2.45 GHz, 32.8 kW/m2; (2) Evaluate the impact of MWT on soil by an ecotoxicological bioassays; (3) Analyze biochemical changes occurring in the roots during the process. A field study was performed to assess the efficacy of S. hogweed control using MWT in times from 2.5 to 15 min. The MWT-treated soil was collected immediately after treatment (AT) and tested using bioassays (Phytotoxkit, Ostracodtoxkit, and Microtox). Fourteen days AT, the MWT hogweed roots were dug out, air-dried, and analyzed for the content and composition of essential oil, sugars, and fatty acids. According to the ecotoxicological biotests, the MWT soils were classified as non-toxic or low-toxic. The regeneration of hogweed was observed only in non-treated plants (control). Hogweed MWT for 2.5-15 min did not regenerate up to 14 days AT. The average weight of roots in hogweed MWT for 15.0 min was ca. two times smaller than the control plants. Those roots contained significantly higher amounts of sugars and saturated fatty acids than the control. We did not find a correlation between S. hogweed root essential oil content and composition and MWT time. The main compounds of essential oil were p­cymene and myristicin. No highly photosensitizing compounds were identified in the tested root oil. We conclude that MWT of S. hogweed could be an environmentally safe and prospective control method, but more studies are needed.

[Surgical treatment in ovarian cancer prevention in carriers of the BRCA1/BRCA2 mutation]. / Postepowanie chirurgiczne w profilaktyce raka jajnika u nosicielek mutacji genów BRCA1/BRCA2.

Ovarian cancer remains to be a real challenge in spite of considerable progress in many areas of modern medicine. The use of genetic testing for detecting mutations of the BRCA genes has been offering clinical scrutiny between mutated versions of the BRCA genes and higher risk of both breast and ovarian cancer A population survey is a method of choice to find out more efficient screening management in order to identify cancer patients who further will be treated effectively early A review of literature on surgical PBSO (prophylactic bilateral salpingooophorectomy) in the BRCA genes mutations carriers with focus on preventive results against morbidity of ovarian cancer has been presented in the article.

Maltodextrin-Coated Peppermint and Caraway Essential Oils Effects on Soil Microbiota.

Essential oils exhibit strong antimicrobial effects that can serve as a substitute for synthetic pesticides. However, many reports mention the use of essential oils in protecting above-ground plant organs and storing raw materials and seeds, but only a few address the effects of treatments on soil microbiota. Regarding this, it is necessary to find a solution that will prevent the rapid degradation of oils in soil and extend the period of their action on the soil microbiota. The solution to this problem can be microencapsulation, where the choice of carrier plays a key role. In our experiment, maltodextrin was studied, often used in the microencapsulation of essential oils. It was examined independently in two doses (M1 and M2, with 50 and 200 g kg-1, respectively) and a combination with two essential oils known for their antimicrobial activity. We hypothesized that the selected microbial communities would react differently to the stress caused by maltodextrin-encapsulated essential oils. The serial dilution method assessed the number of colony-forming units (CFU) of bacteria, fungi, and actinomycetes. As the goal of microencapsulation was to prolong the effect of essential oils, their reaction was observed over a longer period. The soil microbial populations were examined in sandy and loamy soil at 1, 7, 14, and 78 days after encapsulated essential oils were mixed with the soil samples. In both types of soil, a significant increase in bacteria and actinomycetes was observed with maltodextrin in both doses. Encapsulated peppermint and caraway oils had different effects on microbes, both inhibitory and stimulatory. It is also important to note that peppermint with a smaller dose of maltodextrin significantly inhibited the growth of fungi in sandy soil in all measurements, as well as that caraway oil with a higher dose of maltodextrin significantly stimulated the growth of bacteria and actinomycetes in sandy soil. The higher dose of maltodextrin could explain this stimulation. Further research is recommended to test different doses of essential oils and maltodextrin, which would lead to the optimal dose of both wall and core materials.

Intra- and interspecies competition of blackgrass and wheat in the context of herbicidal resistance and environmental conditions in Poland.

Blackgrass (Alopecurus myosuroides Huds.), one of the most aggressive grass weeds in Europe, is also a strong competitor of crops. This study aimed to assess the impact of environmental conditions on the competition between (1) ACC-ase and ALS herbicide-resistant (BR) and herbicide-susceptible (BS) blackgrass biotypes, (2) BR and winter wheat cv. Arkadia (W), and (3) BS and W. In the replacement series model, the experiment was conducted at seven sites across Poland during two seasons (2018/19 and 2019/20). In the BR-BS experiment, the BS biotype was in majority more competitive toward the BR biotype. However, in the regime of optimal hydrothermal conditions and at a higher sand content in the soil we observed a higher competitiveness of BR towards BS. The combined interactions between W and BR or BS were also affected by environmental conditions, i.e., soil texture and hydrothermal coefficient, as explained by PCA and k-means cluster analysis. At most sites, W was more competitive toward both BS and BR, which could result from earlier emergence of W in relation to B in majority of sites. Except for two cases, located on heavy, clay soils, during humid seasons, where B was more competitive toward W. We summarize that blackgrass competitiveness towards other biotypes and wheat depends to some extent on environmental conditions; however, the phenomenon should be explored in more detail.

Cystatin C as a parameter of glomerular filtration rate in patients with ovarian cancer.

AIMS: To evaluate the potential role of serum cystatin C as a marker of renal function in patients with ovarian cancer. METHODS: Treatment of consecutive ovarian cancer patients who were eligible for chemotherapy with paclitaxel (135 mg/m²/24 h) and cisplatin (75 mg/m²) every 3 weeks in 6 cycles. Glomerular filtration rate (GFR) markers, i.e. serum levels of creatinine and cystatin C, estimated by the Cockcroft-Gault and Modification of Diet in Renal Disease formulas, were recorded before each cycle and 3 weeks after the 6th course. RESULTS: The median age of 34 patients was 54 years. In the initial stage of treatment, we did not observe any correlation between cystatin C and other GFR markers. We noted a significant association between cystatin C and tumor extent on spiral CT scans (diameter: >1 cm) performed at baseline (p = 0.004), and after the 1st (p = 0.03) and 2nd cycle (p = 0.026). We observed a correlation between cystatin C and CA-125 level before chemotherapy (R = 0.4; p = 0.02) and after the 1st cycle (R = 0.43; p = 0.04). CONCLUSION: The results of our study suggest that cystatin C is not a reliable marker of the GFR in ovarian cancer patients, probably due to its nature as a cysteine protease inhibitor.

Soil or Vermiculite-Applied Microencapsulated Peppermint Oil Effects on White Mustard Initial Growth and Performance.

Microencapsulated peppermint (Mentha x piperita L.) essential oil (MPEO) is a prospective botanical herbicide. A hypothesis was formulated, that the type of growth medium (vermiculite or silty clay loam soil substrate) affects the phytotoxic potential of MPEO. A pot experiment in a randomized design assessed the effect of five doses of MPEO in a range of 0-108 g m-2 or 0-145 g m-2, mixed with vermiculite or with soil, respectively, on early growth of white mustard (Sinapis alba L. cv. Zlata), tested here as a model "weed" species. The morphologic analyses were supported by selected biochemical measurements. The two highest doses of microcapsules (from 73 to 145 g m-2) caused a significant decrease of plants' height and biomass. An increase of anthocyanin content in the aboveground parts of mustard is supportive for the induction of defense mechanisms against MPEO-triggered stress in mustard leaves. In conclusion, MPEO appears as a promising bio-herbicide. However, we are aware that further studies on the mechanisms of action of MPEO in different weed species are necessary to test (i) whether or not the effect is consistent to be proficiently exploited for weed control in field and (ii) to deepen the biochemical and physiological reactions by the plants against MPEO treatments.

Role of WNT/ß-Catenin Pathway as Potential Prognostic and Predictive Factors in Renal Cell Cancer Patients Treated With Everolimus in the Second and Subsequent Lines.

BACKGROUND: The aim of the present study was to search for predictive and prognostic factors in patients with metastatic renal cell carcinoma (mRCC) treated with everolimus among the components of the WNT/ß-catenin pathway. PATIENTS AND METHODS: In a prospective, single-arm, phase II study, patients with mRCC received everolimus (10 mg/d) in a 30-day cycle. We performed a prospectively planned evaluation of the potential biomarkers of the WNT/ß-catenin pathway. RESULTS: The serum level of soluble E-cadherin (sE-cadherin) in patients with RCC was significantly greater than that in the controls (71.62 ± 22.28 pg/mL vs. 54.26 ± 10.317 pg/mL; P = .0069). After 2 cycles of everolimus therapy, we observed a significance increase in sE-cadherin (from 71.81 ± 21.18 pg/mL to 77.50 ± 28.212 pg/mL; P = .0151). The Dickkopf-1 protein levels in the study and control groups were not significantly different (P = .2135). The favorable independent predictors for everolimus therapy were normal lactate dehydrogenase level before treatment (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.28-0.98; P = .0443) and low sE-cadherin level (HR, 0.54; 95% CI, 0.29-0.98; P = .0422). On multivariate analysis, we observed that worse overall survival was seen in patients with a lower regression coefficient of sE-cadherin after 2 cycles of treatment (HR, 2.60; 95% CI, 1.23-5.52; P = .0128), an increased corrected calcium level (HR, 3.09; 95% CI, 1.21-7.88; P = .0180), and an increased lactate dehydrogenase level before treatment (HR, 1.98; 95% CI, 1.02-3.83; P = .0426). CONCLUSION: WNT/ß-catenin component expression in patients with mRCC had no effect on progression-free survival or overall survival. However, we found that the sE-cadherin level might interact with response to everolimus therapy, although confirmation in future studies is needed.

Cystatin C as a predictor factor in patients with renal cell carcinoma treated by everolimus.

BACKGROUND: We evaluated the influence of serum cystatin C (CysC) with respect to other glomerular filtration rate (GFR) markers on the treatment effect of everolimus in a phase II study in patients with metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: Outcomes were from the study's primary analysis. GFR was calculated according to CKD-EPI-sCr equation, CKD-EPI-CysC equation and CKD-EPI-sCr-CysC equation, Modification of Diet in Renal Disease (MDRD) equation and Cockcroft-Gault (CG) equation, serum levels of creatinine (sCr) and CysC before the treatment. RESULTS: We observed in 56 patients analysed patients high correlation (R Spearman from ±0.69 to ±1.00; P < 0.0001) between CysC level and GFR markers: sCr, CKD-EPI-sCr, CKD-EPI-CysC, CKD-EPI-sCr-CysC, MDRD, GFR (CG) before everolimus therapy. We observed that the adverse independent predictors for everolimus therapy were increased CysC level [HR: 2.85 (95 % CI 1.34-6.05), P = 0.0065], histologic grade G1/2 [HR: 3.38 (95 % CI 1.59-7.20), P = 0.0016] and increased LDH level [HR: 5.59 (95 % CI 2.52-12.40), P < 0.0001]. Worse OS was seen in multivariate analysis in patients with increased cystatin C level before treatment [HR: 2.60 (1.03-2.60), P = 0.0428], increased corrected calcium level [HR: 2.78 (95 % CI 1.03-7.54), P = 0.0441] and increased LDH level before treatment [HR: 2.34 (95 % CI 1.11-4.97), P = 0.0262]. CONCLUSION: Increased serum CysC level in contrast to other studied GFR markers had predictive significance in patients with mRCC.