Stefan Galbavy

Background: Bladder cancer exhibits substantial heterogeneity, and accurate discrimination between non-muscle-invasive (NMIBC) and muscle-invasive disease (MIBC), as well as between low-grade (LG) and high-grade (HG) tumors, remains essential for appropriate clinical management. Established immunohistochemical (IHC) markers, such as p53, Ki-67, and E-cadherin, could be used in a new setting, but standardized cut-off values and their combined predictive value remain unclear. This study aimed to identify optimal cut-offs for these markers and to evaluate whether biomarker combinations enhance the discrimination of tumor grade and stage. Methods: A retrospective dataset of 568 cases of bladder cancer was analyzed. For each case, the expression of p53, Ki-67, and E-cadherin was quantified, and tumors were classified as NMIBC or MIBC, and as LG or HG. ROC-based cut-off selection was performed using Youden’s J criterion with 10-fold stratified cross-validation. E-cadherin was modelled using an inverted scale to reflect biological loss. Logistic regression models were used to evaluate the discriminatory performance of single markers, two-marker combinations, and a three-marker model. Cross-validated AUC values and optimal thresholds were reported. Results: Ki-67 showed the strongest single-marker performance for predicting both MIBC (AUC 0.842) and HG disease (AUC 0.813), with optimal cut-offs of ≥40% and ≥30%, respectively. p53 demonstrated moderate discrimination (AUC 0.778 for MIBC and 0.776 for HG), while E-cadherin, evaluated on an inverted scale, showed acceptable performance (AUC 0.746 for MIBC; 0.780 for HG). Combining markers yielded modest improvements, with the best performance observed for Ki-67 + E-cadherin (AUCs of 0.851 for MIBC and 0.838 for HG). Conclusions: Ki-67 is the most effective single biomarker for distinguishing invasive and HG bladder cancer, while E-cadherin provides complementary value. A two-marker panel combining Ki-67 and E-cadherin, using appropriate cut-offs, offers the highest overall performance and may serve as a practical tool for enhanced pathological stratification.

Although the incidence varies with age and gender, urothelial bladder cancer is a relatively frequently occurring malignancy with variable clinical behavior that often has high recurrence rates. In this study, we analyzed the tumor tissues of 224 patients with pTa, pT1, and pT2 urinary bladder cancer. We performed a histomorphologic analysis and immunohistochemistry for p53, Ki-67, and E-cadherin, which were selected as markers of the malignant process. For pTa and pT1, univariate analyses of cancer-specific survival (CSS), progression-free survival (PFS), and recurrence-free survival (RFS) were calculated using the Kaplan-Meier method, the log-rank test and Cox regression. Multivariate analysis was performed by a Cox regression analysis. Ki-67 (P<0.001) was significantly associated with CSS, but the highest association was shown for E-cadherin (P<0.001). For pT1 and pTa, the Kaplan-Meier analysis and the log-rank test revealed significantly worse PFS for patients with higher levels of Ki-67 (P<0.001) and lower levels of E-cadherin (P<0.001). Based on these obtained results, it can be clearly stated that Ki-67 and E-cadherin expression levels are associated with CSS, PFS and RFS. The clinical utility of these markers is valuable for pTa and pT1 urinary bladder cancer and should be further verified with prospective multi-center trials.

Bone metastases in neuroendocrine tumors

While the hydroxyl radical (^•OH) in the snowpack is likely a dominant oxidant for organic species and bromide, little is known about the kinetics or steady-state concentrations of ^•OH on/in snow and ice. Here we measure the formation rate, lifetime, and concentration of ^•OH for illuminated polar snow samples studied in the laboratory and in the field. Laboratory studies show that ^•OH kinetics and steady-state concentrations are essentially the same for a given sample studied as ice and liquid; this is in contrast to other photooxidants, which show a concentration enhancement in ice relative to solution as a result of kinetic differences in the two phases. The average production rate of ^•OH in samples studied at Summit, Greenland, is 5 times lower than the average measured in the laboratory, while the average ^•OH lifetime determined in the field is 5 times higher than in the laboratory. These differences indicate that the polar snows we studied in the laboratory are affected by contamination, despite significant efforts to prevent this; our results suggest similar contamination may be a widespread problem in laboratory studies of ice chemistry. Steady-state concentrations of ^•OH in clean snow studied in the field at Summit, Greenland, range from (0.8 to 3) × 10⁻¹⁵ M, comparable to values reported for midlatitude cloud and fog drops, rain, and deliquesced marine particles, even though impurity concentrations in the snow samples are much lower. Partitioning of firn air ^•OH to the snow grains will approximately double the steady-state concentration of snow-grain hydroxyl radical, leading to an average [^•OH] in near-surface, summer Summit snow of approximately 4 × 10⁻¹⁵ M. At this concentration, the ^•OH-mediated lifetimes of organics and bromide in Summit snow grains are approximately 3 days and 7 h, respectively, suggesting that hydroxyl radical is a major oxidant for both species.

Amifostine protects normal cells from DNA damage induction by ionizing radiation or chemotherapeutics, whereas cancer cells typically remain uninfluenced. While confirming this phenomenon, we have revealed by comet assay and currently the most sensitive method of DNA double strand break (DSB) quantification (based on γH2AX/53BP1 high-resolution immunofluorescence microscopy) that amifostine treatment supports DSB repair in γ-irradiated normal NHDF fibroblasts but alters it in MCF7 carcinoma cells. These effects follow from the significantly lower activity of alkaline phosphatase measured in MCF7 cells and their supernatants as compared with NHDF fibroblasts. Liquid chromatography–mass spectrometry confirmed that the amifostine conversion to WR-1065 was significantly more intensive in normal NHDF cells than in tumor MCF cells. In conclusion, due to common differences between normal and cancer cells in their abilities to convert amifostine to its active metabolite WR-1065, amifostine may not only protect in multiple ways normal cells from radiation-induced DNA damage but also make cancer cells suffer from DSB repair alteration.

Retinoids have shown potential for the inhibition of tumour growth and progression. The objective of this study was to investigate retinoic acid nuclear receptor subtypes RAR/RXR and iodothyronine 5'-deiodinase, type I expression pattern in papillary thyroid tumour tissue of 26 patients in order to compare with those of the non-neoplastic thyroid tissue of the corresponding patients. The expression of selected parameters mRNA was examined by semi-quantitative RT-PCR. Papillary thyroid carcinoma (PTC) expressed RXRγ, when compared to non-neoplastic thyroid tissues of the corresponding patients that were lacking expression of RXRγ or its expression was very low. Moreover, we found significantly increased expression of RARα and RARγ in the overall group of PTC. This increase was detected in cases with positive lymph node metastasis (LNM), but not in cases with negative LNM. RARβ was significantly reduced in the subgroup of classic variant (CV). We also detected absence or significantly lower expression of hDIO1 mRNA in tumour tissue when compared to non-neoplastic tissue in both overall PTC cases and in the CV subgroup. However, the significantly decreased levels of hDIO1 mRNA were detected in cases with negative LNM but not in cases with positive LNM when compared to corresponding non-tumour tissue in both overall PTC cases and in the CV subgroup. Differences in RAR and RXR subtype mRNA expression patterns in various PTCs may contribute to the immunochemistry data available, and may thus find exploitation in clinical oncology, particularly in the differential diagnosis of thyroid neoplasms.

Breast cancer is the most common cancer in women worldwide, representing 28.2% of all female malignancies. In addition to genetic changes, epigenetic events, as aberrant DNA methylation and histone modification, are responsible for cancer development

Sertoli-Leydig cell tumor is a rare and usually unilateral tumor of the ovary occurring in women's reproductive age. Only about 10% of these patients are over 50 years of age. One third of these patients are suffering from signs of virilisation. This work summarizes the morphological and immunohistochemical characteristics of this tumor in a 56-year old woman with clinical signs of virilisation.

The tumor suppressor gene p53 is a key regulator of cell division and/or apoptosis. Survivin is a multifunctional member of the inhibitor of apoptosis family. Survivin and p53 represent diametrically opposed signals that influence the apoptotic pathway. To determine the role of p53 and survivin in basal cell carcinoma (BCC), we evaluated the expression pattern of both proteins with regard to the percentage of positively immunostained tumor cells, the intensity of staining, and subcellular localization among 31 subjects with BCC. Overexpression of p53 protein was found in 28 of 31 cases (90.3%), whereas survivin accumulation was seen in 27 (87.1%). For p53, moderate and/or strong immunoreactivity was seen in 20 of 28 cases (71.4%), and 26 of 28 cases (92.9%) showed more than 25% reactive tumor cells. Nuclear p53 staining was detected in 23 of 28 cases (82.1%), whereas combined nuclear and cytoplasmic localization was found in only 5 of 28 cases (17.9%). Survivin revealed mild intensity of immuno-reaction in 22 of 27 cases (71%), and 25 of 27 cases (92.6%) showed less than 25% labeled tumor cells. Combined nuclear and cytoplasmic survivin localization was present in 26 of 27 cases (96.3%). Statistically significant differences were detected in the assessed expression parameters between those proteins. Our results suggest that overexpression of wild type p53 protein may suppress the expression of survivin and its antiapoptotic activity in BCC cells.