Showing papers by "Cezary Szczylik published in 2018"

Pembrolizumab monotherapy as first-line therapy in advanced clear cell renal cell carcinoma (accRCC): Results from cohort A of KEYNOTE-427.

Abstract: 4500Background: Programmed death-1 (PD-1) inhibitor–based combination therapy shows clinical benefit in first-line accRCC However, data are limited on clinical impact of first-line PD-1 inhibitor

Surface markers of cancer stem-like cells of ovarian cancer and their clinical relevance.

Abstract: Cancer stem-like cells (CSLCs) are defined as cancer cells with stem cell characteristics. Although CSLCs constitute no more than a few percent of the tumor mass, they play important roles in cancer chemo-resistance, metastasis and disease recurrence. Ovarian cancer (OC) is considered the most aggressive gynecological malignancy in which the role of CSLCs is of major significance, although it remains to be specified. The studies describing ovarian CSLC phenotype vary in the definition of the molecular pattern of expression of the main markers such as CD133, CD44, CD117, and CD24. Stem-like features of OC have been shown to correlate with the clinical course of the disease and permit diagnosis, prognosis and treatment outcome to be improved. Identification of CSLC markers could provide hallmarks which, related to the chemo-resistance of the disease, will facilitate treatment selection. This review describes recent advances in research on stem-like cell status in OC, mainly focusing on surface markers of CSLCs and their clinical relevance.

Involvement of the CB2 cannabinoid receptor in cell growth inhibition and G0/G1 cell cycle arrest via the cannabinoid agonist WIN 55,212-2 in renal cell carcinoma.

Abstract: The anti-tumor properties of cannabinoids have been investigated in many in vitro and in vivo studies. Many of these anti-tumor effects are mediated via cannabinoid receptor types 1 and 2 (CB1 and CB2), comprising the endocannabinoid system (ECS). In this study, we investigated the ECS based on CB 1 and CB 2 receptor gene and protein expression in renal cell carcinoma (RCC) cell lines. In view of their further use for potential treatments, we thus investigated the roles of CB1 and CB2 receptors in the anti-proliferative action and signal transduction triggered by synthetic cannabinoid agonists [such as JWH-133 and WIN 55,212–2 (WIN-55)] in RCC cell lines. Human RCC cell lines were used for this study. The CB 1 and CB 2 gene expression levels were analyzed using real-time PCR. Flow cytometric, immunocytochemical and western blot analyses were performed to confirm CB1 and CB2 receptor protein expression. The anti-proliferative effects of synthetic cannabinoids were investigated on cell viability assay. The CB1 and CB2 receptors were blocked pharmacologically with the antagonists SR141716A and AM-630, respectively, to investigate the effects of the agonists JWH-133 and WIN-55. Cell cycle, apoptosis and LDH-based cytotoxicity were analyzed on cannabinoid-treated RCC cells. The CB1 and CB2 genes expression was shown by real-time PCR and flow cytometric and western blot analysis indicating a higher level of CB2 receptor as compared to CB1 in RCC cells. Immunocytochemical staining also confirmed the expression of the CB1 and CB2 proteins. We also found that the synthetic cannabinoid agonist WIN-55 exerted anti-proliferative and cytotoxic effects by inhibiting the growth of RCC cell lines, while the CB2 agonist JWH-133 did not. Pharmacologically blocking the CB1 and CB2 receptors with their respective antagonists SR141716A and AM-630, followed by the WIN-55 treatment of RCC cells allowed uncovering the involvement of CB2, which led to an arrest in the G0/G1 phase of the cell cycle and apoptosis. This study elucidated the involvement of CB2 in the in vitro inhibition of RCC cells, and future applications of CB2 agonists in the prevention and management of RCC are discussed.

Opening an onconephrology clinic: recommendations and basic requirements.

Abstract: Onconephrology is a rapidly evolving subspeciality that covers all areas of renal involvement in cancer patients. The complexity of the field may benefit from well-defined multidisciplinary management administered by a dedicated team. Since there is an increasing need to address the needs of this population in dedicated outpatient clinics, it is critical to highlight basic characteristics and to suggest areas of development. In this brief perspective article, we analyse the requirements of an onconephrology clinic in terms of logistics, critical mass of patients and building a multidisciplinary team. We will further discuss which patients to refer and which conditions to treat. The last part of the article is dedicated to education and performance indicators and to analysis of the potential advantages of applying the hub-and-spoke model to this field. The ultimate aim of this experience-based article is to initiate debate about what an onconephrology outpatient clinic might look like in order to ensure the highest quality of care for this growing population of patients.

Prognostic Significance of Pancreatic Metastases from Renal Cell Carcinoma in Patients Treated with Tyrosine Kinase Inhibitors.

Abstract: AIM The study aimed to define the true impact of pancreatic metastases (PM) from renal cell carcinoma on overall survival (OS) in patients treated with first-line tyrosine kinase inhibitors. PATIENTS AND METHODS Overall, 321 consecutive patients were analysed. The influence of PM on OS was assessed using the Kaplan-Meier estimator and the log-rank test (unadjusted and adjusted) and two multivariabe Cox proportional hazards regressions (CPHR). RESULTS Thirty-four patients (10%) had PM and 287 (90%) had sites of metastasis other than the pancreas; the median OS was 46.1 and 23.1 months, respectively (unadjusted log-rank p=0.020; adjusted log-rank p=0.544). The PM status was an insignificant factor for OS in both CPHR (hazard ratio(HR)=0.84, p=0.603, and HR=0.66, p=0.098). CONCLUSION The presence of PM was not an independent prognostic factor, but was rather an indicator of an indolent course of the disease.

Immune consequences of anti-angiogenic therapyin renal cell carcinoma.

Abstract: Current therapies of renal cell carcinoma (RCC), a highly vascularised tumour, mostly rely on anti-angiogenic treatment options. These include tyrosine kinase inhibitors (TKIs) and anti-VEGF monoclonal antibodies. Although these strategies aim at restraining vascularisation to control tumour growth, the effects of such therapies are much wider, as affecting the vessel structure deeply modifies the microenvironment of the tumour mass. The aim of this review is to provide an overview of current knowledge on the global effects of anti-angiogenic treatment, mostly TKIs, on the shaping of the immune component of the RCC microenvironment. The data supporting the modification of immunity by anti-angiogenic therapies are collected to reveal the potential of angiogenesis modulation as a strategy for the adjuvant anti-cancer approach in immunotherapy.

Culture in embryonic kidney serum and xeno-free media as renal cell carcinoma and renal cell carcinoma cancer stem cells research model.

Abstract: The use of fetal bovine serum hinders obtaining reproducible experimental results and should also be removed in hormone and growth factor studies. In particular hormones found in FBS act globally on cancer cell physiology and influence transcriptome and metabolome. The aim of our study was to develop a renal carcinoma serum free culture model optimized for (embryonal) renal cells in order to select the best study model for downstream auto-, para- or endocrine research. Secondary aim was to verify renal carcinoma stem cell culture for this application. In the study, we have cultured renal cell carcinoma primary tumour cell line (786-0) as well as human kidney cancer stem cells in standard 2D monolayer cultures in Roswell Park Memorial Institute Medium or Dulbecco's Modified Eagle's Medium and Complete Human Kidney Cancer Stem Cell Medium, respectively. Serum-free, animal-component free Human Embryonic Kidney 293 media were tested. Our results revealed that xeno-free embryonal renal cells optimized culture media provide a useful tool in RCC cancer biology research and at the same time enable effective growth of RCC. We propose bio-mimic RCC cell culture model with specific serum-free and xeno-free medium that promote RCC cell viability.

Effect of Everolimus on Heterogenous Renal Cancer Cells Populations Including Renal Cancer Stem Cells.

Abstract: The aim of this study was to compare effect of everolimus on growth of different renal cell carcinoma (RCC) populations and develop experimental design to measure the early response of everolimus in clear cell RCC (ccRCC) cell lines including renal cancer stem cells. Effect of everolimus on RCC cell lines which include primary (786-0) and metastatic (ACHN) RCC cell lines as well as heterogenous populations of tumor cells of different histological RCC subtypes (clear cell RCC and papillary RCC) was measured when treated with everolimus in the range of 1–9 µM. Gene expression profiling using microarray was performed to determine the early response to everolimus in ccRCC cell lines after optimizing concentration of drug. Gene Set Enrichment Analysis (GSEA) was done which mainly focused on basic genes related to mTOR, hormonal and metabolic pathways. Everolimus acts on RCC cells in a dose—dependent manner. In all examined cell lines IC50 dose was possible to calculate after the third day of treatment. In ccRCC lines (parental and stem cell) everolimus changes expression of mTOR complexes elements and elements of related pathways when treated with optimized doses of drug. Characteristic expression profile for ccRCC cells at an early exposure time to everolimus is to elucidate. Wevarie include some basic observations derived from data analysis in the context of mechanism of action of drug with a view to better understand biology of renal cancer cells.

Biomarkers defining probability of receiving second-line targeted therapy in metastatic renal cell carcinoma.

Abstract: In order to facilitate long-term treatment decisions, we aimed to define biomarkers defining the probability of receiving second-line (SL) targeted therapy (TT) in patients with metastatic renal cell carcinoma (mRCC) based on their characteristics present at first-line TT initiation. We analysed 152 consecutive mRCC patients treated and used multivariable binominal logistic regression to identify factors contributing to the probability of receiving SL TT. Final model was assessed with bias-corrected indices (Nagelkerke’s R2 and area under receiver operating characteristic curve [AUC]) and two bootstrap procedures were used for internal validation. Factors associated with the probability of SL TT eligibility were the presence of brain metastases (odds ratio [OR] 0.084, 95% confidence interval [CI] 0.010–0.707), number of metastatic sites (OR 0.740, 95% CI 0.575–0.953 per each site), platelet count (OR 0.971, 95% CI 0.947–0.997, per 104/ml), lactate dehydrogenase level (OR 0.952, 95% CI 0.910–0.997 per 10 units/l), and albumin concentration (OR 1.924, 95% CI 1.057–3.503 per 1 g/dl). We developed on-line calculator that enables practicing clinicians to estimate SL treatment probability ( http://www.r-calc.com ).