Addition of Chromosome 17 Polysomy and HER2 Amplification Status Improves the Accuracy of Clinicopathological Factor-Based Progression Risk Stratification and Tumor Grading of Non-Muscle-Invasive Bladder Cancer.

Progression of non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive disease (MIBC) significantly worsens life expectancy. Its risk can be assessed by clinicopathological factors according to international guidelines. However, additional molecular markers are needed to refine and improve the prediction. Therefore, in the present study, we aimed to predict the progression of NMIBCs to MIBC by assessing p53 expression, polysomy of chromosome 17 (Chr17) and HER2 status in the tissue specimens of the tumors of 90 NMIBC patients. Median follow-up was 77 months (range 2−158). Patients with Chr17 polysomy or HER2 gene amplification had a higher rate of disease progression (hazard ratio: 7.44; p < 0.001 and 4.04; p = 0.033, respectively; univariate Cox regression). Multivariable Cox regression models demonstrated that the addition of either Chr17 polysomy or HER2 gene amplification status to the European Association of Urology (EAU) progression risk score increases the c-index (from 0.741/EAU/ to 0.793 and 0.755, respectively), indicating that Chr17 polysomy/HER2 amplification status information improves the accuracy of the EAU risk table in predicting disease progression. HER2/Chr17 in situ hybridization can be used to select non-progressive cases not requiring strict follow-up, by reclassifying non-HER2-amplified, non-polysomic NMIBCs from the high- and very high-risk groups of EAU to the intermediate-risk group.

High Pretreatment Serum PD-L1 Levels Are Associated with Muscle Invasion and Shorter Survival in Upper Tract Urothelial Carcinoma.

Programmed death ligand-1 (PD-L1) is an immune checkpoint molecule and a widely used therapeutic target in urothelial cancer. Its circulating, soluble levels (sPD-L1) were recently suggested to be associated with the presence and prognosis of various malignancies but have not yet been investigated in upper tract urothelial carcinoma (UTUC). In this study, we assessed sPD-L1 levels in 97 prospectively collected serum samples from 61 UTUC patients who underwent radical nephroureterectomy (RNU), chemotherapy (CTX), or immune checkpoint inhibitor (ICI) therapy. In addition to pretreatment samples, postoperative and on-treatment sPD-L1 levels were determined in some patients by using ELISA. In the RNU group, elevated preoperative sPD-L1 was associated with a higher tumor grade (p = 0.019), stage (p < 0.001) and the presence of metastasis (p = 0.002). High sPD-L1 levels were significantly associated with worse survival in both the RNU and CTX cohorts. sPD-L1 levels were significantly elevated in postoperative samples (p = 0.011), while they remained unchanged during CTX. Interestingly, ICI treatment caused a strong, 25-fold increase in sPD-L1 (p < 0.001). Our results suggest that elevated preoperative sPD-L1 level is a predictor of higher pathological tumor stage and worse survival in UTUC, which therefore may help to optimize therapeutic decision-making. The observed characteristic sPD-L1 flare during immune checkpoint inhibitor therapy may have clinical significance.

Androgen Receptor Splice Variants Contribute to the Upregulation of DNA Repair in Prostate Cancer.

BACKGROUND: Canonical androgen receptor (AR) signaling regulates a network of DNA repair genes in prostate cancer (PCA). Experimental and clinical evidence indicates that androgen deprivation not only suppresses DNA repair activity but is often synthetically lethal in combination with PARP inhibition. The present study aimed to elucidate the impact of AR splice variants (AR-Vs), occurring in advanced or late-stage PCA, on DNA repair machinery. METHODS: Two hundred and seventy-three tissue samples were analyzed, including primary hormone-naïve PCA, primary metastases, hormone-sensitive PCA on androgen deprivation therapy (ADT) and castration refractory PCA (CRPC group). The transcript levels of the target genes were profiled using the nCounter platform. Experimental support for the findings was gained in AR/AR-V7-expressing LNCaP cells subjected to ionizing radiation. RESULTS: AR-Vs were present in half of hormone-sensitive PCAs on androgen deprivation therapy (ADT) and two-thirds of CRPC samples. The presence of AR-Vs is highly correlated with increased activity in the AR pathway and DNA repair gene expression. In AR-V-expressing CRPC, the DNA repair score increased by 2.5-fold as compared to AR-V-negative samples. Enhanced DNA repair and the deregulation of DNA repair genes by AR-V7 supported the clinical data in a cell line model. CONCLUSIONS: The expression of AR splice variants such as AR-V7 in PCA patients following ADT might be a reason for reduced or absent therapy effects in patients on additional PARP inhibition due to the modulation of DNA repair gene expression. Consequently, AR-Vs should be further studied as predictive biomarkers for therapy response in this setting.

Elevated Pre-Treatment Serum MMP-7 Levels Are Associated with the Presence of Metastasis and Poor Survival in Upper Tract Urothelial Carcinoma.

Upper tract urothelial carcinoma (UTUC) is a rare cancer with a barely predictable clinical behaviour. Serum MMP-7 is a validated prognostic marker in urothelial bladder cancer, a tumour entity with large clinical, histological, and molecular similarity to UTUC. The serum MMP-7 levels have not yet been investigated in UTUC. In the present study, we determined MMP-7 concentrations in an overall number of 103 serum samples from 57 UTUC patients who underwent surgical or systemic (platinum or immune checkpoint inhibitor) therapy by using the ELISA method. In addition to pre-treatment samples, the serum samples collected at predefined time points after or during therapy were also investigated. Serum MMP-7 concentrations were correlated with clinicopathological and follow-up data. Our results revealed significantly, two-fold elevated pre-treatment serum MMP-7 levels in metastatic cases of UTUC in both the radical surgery- and the chemotherapy-treated cohorts (p = 0.045 and p = 0.040, respectively). In addition, high serum MMP-7 levels significantly decreased after radical surgery, and high pre-treatment MMP-7 concentrations were associated with shorter survival both in the surgery- and chemotherapy-treated cohorts (p = 0.029 and p = 0.001, respectively). Our results revealed pre-treatment serum MMP-7 as a prognostic marker for UTUC, which may help to improve preoperative risk-stratification and thereby improve therapeutic decision-making.

[Local care and systemic drug treatment of non-muscle invasive bladder tumors]. / Nem izominvazív húgyhólyagdaganatok lokális ellátása és szisztémás gyógyszeres kezelése.

Bladder cancer is the most common malignancy of the urinary tract. It can be divided into non-muscle invasive and muscle-invasive groups according to depth of tumor invasion. Based on the significant differences regarding their biological behavior, propensity to progress, and therapy responsiveness these two groups are discussed seperately. Treatment of non-muscle invasive bladder cancers has traditionally been performed by urologists, but recent advances in the field predict that clinical oncologists may have a more intense role in high-risk non-muscle invasive cases. In the present study, we summarize the current surgical and pharmacological treatment options for non-muscle invasive bladder cancer.

Molecular underpinnings of systemic treatment resistance in metastatic castration-resistant prostate cancer / [Az áttétes kasztrációrezisztens prosztatarák gyógyszer-rezisztenciájának molekuláris vonatkozásai]

In the last few years, several new drugs with various mechanisms of action have been approved for the treatment of castration-resistant prostate cancer. Due to this development, therapeutic decision-making has become increasingly complex. Therefore, therapy selection as well as timing and sequence of treatments need to be optimized in an individual manner. In addition, also for these novel therapies, baseline and acquired as well as cross-resistance have been observed. Underlying mechanisms become increasingly clear, resulting in a shift from empiric-based towards rational-based therapeutic decision-making. In the present review, we provide an overview on the resistance mechanisms against the most frequently applied systemic treatments of metastatic castration-resistant prostate cancer such as docetaxel, abiraterone and enzalutamide. We summarize - among others - the mechanisms by MDR (multidrug-resistant) protein expression, alterations of androgen receptor, Wnt, p53 and DNA-repair pathways (BRCA/ATM) as well as resistance through therapy-induced neuroendocrine differentiation of the tumour. Orv Hetil. 2020; 161(20): 813-820.

Characteristics of bladder recurrence after radical nephroureterectomy in upper urinary tract cancer / A húgyhólyag-recidíva jellemzoi felso üregrendszeri daganatos betegekben radikális ureteronephrectomia után

INTRODUCTION: Urothelial cancer can develop in the renal pelvis, ureters, bladder and the proximal urethra as urothelial tissue can be found in these organs. Upper tract urothelial carcinoma is rare but better understanding of the natural history of the disease is important because bladder recurrence often occurs after radical nephroureterectomy. AIM AND METHOD: Our retrospective study aims to describe the general characteristics of patients treated with radical nephroureterectomy at the Department of Urology, Semmelweis University, between January 1st, 2005 and December 31st, 2016. Additionally, we aimed to identify risk factors of bladder recurrence after radical surgery. RESULTS: 160 patients had radical nephroureterectomy and 135 of them had urothelial upper urinary tract cancer. The mean follow-up period was 32 months (SD: 30.25), bladder recurrence was diagnosed at 31 patients (23%), the average time for the recurrence was 19.6 months (SD: 29.7). Recurrence occurred significantly earlier among older patients (p = 0.007) and it was also associated with hypertonia of the patients (p = 0.035). CONCLUSION: Upper tract urothelial cancer recurrence occurs earlier among older and multimorbid patients. Careful watching of these patients (frequent reminder to regular cystoscopy and control examinations) could reduce further complications. Orv Hetil. 2020; 161(21): 881-888.

Development and Initial Testing of a Modified UroVysion-Based Fluorescence In Situ Hybridization Score for Prediction of Progression in Bladder Cancer.

OBJECTIVES: Our aim was to predict progression of non-muscle-invasive bladder urothelial carcinomas (NMIUCs) into muscle-invasive disease by assessing cytogenetic abnormality of tumors with a new UroVysion scoring system. METHODS: Seventy-five bladder cancer cases (including 57 NMIUCs) were classified according to the quantitatively assessed degree of UroVysion-detected chromosomal abnormalities into urine fluorescence in situ hybridization score (UFS) groups: UFS I, II, and III. Cox time-to-event, Kaplan-Meier, and C-statistics analyses were performed. RESULTS: UFS proved to be an independent prognostic factor of progression-free survival (PFS) and time to progression (TTP). NMIUCs with UFS III had a 34.05-fold increased hazard for progression to muscle-invasive cancer (TTP; 95% confidence interval, 5.841-198.5; P < .001) in comparison with UFS I to II cases. The addition of UFS to conventional risk scores increased the C-index for PFS and TTP. CONCLUSIONS: UFS can indicate an increased risk for progression into muscle-invasive disease in patients with NMIUC and improves prognostic accuracy of the current clinical risk assessment systems.

[Molecular subtype classification of urothelial bladder cancer and its clinical relevance]. / A húgyhólyag urothelialis daganatainak molekuláris alcsoportbeosztása és annak klinikai vonatkozásai.

Current advances in molecular techniques and bioinformatics allowed the analysis of complex molecular patterns in various cancers including muscle-invasive bladder cancer. As a consequence, in the last few years numerous gene- and protein expression-based molecular classifications have been recommended. Recently a comprehensive consensus classification for muscle-invasive urothelial bladder cancer has been published, distinguishing 6 subgroups with a potential impact on clinical decision-making. At the same time, the therapeutic landscape of muscle-invasive bladder cancer becomes increasingly differentiated as novel checkpoint inhibitors have been available for cisplatin-ineligible and/or resistant patients. Furthermore, promising results have been obtained with FGFR targeting agents. Therefore, molecular subtyping will probably have a crucial role in individualized therapeutic decision-making in bladder cancer. In the present work, we summarize the evolution, recent advances and potential therapeutic relevance of molecular subclassifications in bladder cancer. Orv Hetil. 2019; 160(42): 1647-1654.

Circulating and tissue IMP3 levels are correlated with poor survival in renal cell carcinoma.

Tissue protein expression of IMP3 is emerging as a promising prognostic factor in renal cell carcinoma (RCC). The most commonly used immunohistochemical (IHC) antibody has been criticized for its low specificity. In addition, blood levels of IMP3 have not yet been analyzed in RCC. Therefore, we compared the prognostic performance of two different IMP3 IHC antibodies and assessed the prognostic relevance of IMP3 plasma levels in RCC. IMP3 levels were assessed in an overall number of 425 RCC (344× clear cell [ccRCC], 63× papillary [pRCC], 18× chromophobe [chRCC]) patients in three partly overlapping cohorts. Plasma IMP3 concentrations were determined by ELISA in 98 RCC (79× ccRCC, 15× pRCC, 4× chRCC) patients and 20 controls. IMP3 mRNA expression levels were analyzed in 73 frozen tissue samples (55× ccRCC, 12× pRCC, 6× chRCC), while protein expressions were assessed in 366 FFPE samples (294× ccRCC, 56× pRCC, 16× chRCC) using the M3626 and N-19 antibodies. IMP3 plasma and mRNA expression levels were significantly higher in patients compared to controls and in high-grade compared to low-grade tumors. In addition, IMP3 plasma and tissue protein levels (by M3626) were higher and IMP3 mRNA expression levels tended to be higher in patients with distant metastasis. Multivariate analyses in clear cell RCC revealed high IMP3 plasma concentration and mRNA expression as independent predictors of disease-specific survival. IMP3 immunostainings by M3626 but not by N-19 were independently associated with poor overall and disease-specific survival. High plasma and tissue levels of IMP3 are independently associated with poor RCC prognosis. The applied antibody significantly impacts the prognostic performance of analysis. IMP3 analysis may improve risk-stratification of RCC patients and therefore could help to optimize therapeutic and follow-up decisions.

Long-term costs and survival of prostate cancer: a population-based study.

PURPOSE: There is a rising interest in measuring the societal burden of malignancies including prostate cancer. However, population-based studies reporting incidence costs of prostate cancer in the long term are lacking in Europe. The objectives of the study are to analyse the long-term costs and survival of prostate cancer patients treated by radical prostatectomy (RP) or conservative management (nRP). METHODS: A retrospective claims data analysis of the National Health Insurance Found Administration of Hungary between 01.01.2002 and 31.10.2013 was carried out. Annual incidence costs related to prostate cancer and overall survival were calculated for a cohort of patients diagnosed between 2002 and 2005. RESULTS: Altogether 17,642 patients were selected; 2185 (12%) of them have undergone RP. The annual incidence rate ranged between 4177 and 4736 cases. Mean age of RP and nRP patients was 59.4 (SD 5.9) and 71.0 (8.4) years, respectively. The mean survival time of the RP patients was significantly longer compared to nRP patients both in the total sample (11.2 vs. 7.4 years; p < 0.001) and in the subgroup <70 years (11.3 vs. 8.8 years; p < 0.001). At the end of the 12-year follow-up, RP patients had a higher (0.83 vs. 0.68), while nRP patients had a slightly lower (0.35 vs. 38) probability of being alive compared with the age-matched general male population. The long-term cumulative costs of the RP and nRP patients amounted to €4448 and €8616. The main driver of the cost difference was the high drug costs in the nRP group. CONCLUSIONS: To our knowledge, this study applied the longest time-window in reporting population-based incidence costs in Europe. We found that not only RP patients lived longer but they had significantly lower total long-term costs than nRP patients. Therefore, radical prostatectomy is a cost-effective strategy in prostate cancer.

[Novelties in diagnostics and treatment of prostate cancer]. / Újdonságok a prosztatarák diagnosztikájában és kezelésében.

Similarly to earlier years, a vast majority of novel findings were published on prostate cancer, which is the most common urological cancer. Clinical trials with long-term follow-up and promising observational studies were published. In this paper the author reviews the relevant novelties including the diagnostic use of magnetic resonance imaging and positron emission tomography/computed tomography as well as active surveillance, cytoreductive prostatectomy and medical treatment.

[Significance of positive surgical margin in radical prostatectomy]. / A pozitív sebészi szél jelentõsége radikális prosztatektómia esetén.

The optimal oncological result of radical prostatectomy (RP) is complete removal of the prostate gland and seminal vesicles with negative surgical margins. Preoperative diagnostic biopsies are examined and reported by the pathologist according to standardized rules. Staging of the disease is based on modern preoperative image analysis, most commonly multiparametric MRI. Pathological assessment and reporting of RP specimens is based on the International Society of Uropathology guidelines issued by the 2009 Consensus Conference. Positive surgical margin (PSM) is reported by the pathologist in approximately 1/3rd of RP cases. PSM increases the risk of biochemical, local and systemic progression. Pseudo-whole mount assessment of these specimens is the basis for radio-pathological correlation, thus providing quality control for preoperative MRI as well as assisting preoperative image analysis, sampling and diagnostic workup.

The influence of expertise of the surgical pathologist to undergrading, upgrading, and understaging of prostate cancer in patients undergoing subsequent radical prostatectomy.

PURPOSE: The main objective of this retrospective study was to evaluate the influence of pathological experience in histological examination of prostate cancer (PCa) on preoperative understaging (UNS), undergrading (UNG), and upgrading (UPG). METHODS: Histopathological data of prostate biopsy (PB) and radical prostatectomy (RP) specimens of patients undergoing subsequent radical prostatectomy (n = 430) in our center were compared. Histological diagnoses of PB were provided either by corresponding academic pathology institute (Group 1: 322 patients) or by external (nonacademic) departments which had a lower number (≤ 100/year) of PCa histopathological evaluations (Group 2 108 patients). The rate of UNG, UPG, and UNS in both groups and also the effects of institutional learning curve were analyzed in terms of grading and staging. RESULTS: Significant difference was detected between Group 1 and Group 2 in average preoperative Gleason score (GS) values and in the rate of well, moderately, and poorly differentiated cancers as well. There was also a significant difference in the rate of UNG (29.1 vs. 56.5 %, p < 0.0001). The mean preoperative and postoperative GS in Group 1 was significantly lower in the first 50 than in the last 50 patients, but the rates of UNG, UPG, and UNS did not differ significantly between the groups. CONCLUSIONS: The experience of pathologists has direct influence on grading concordance and on UNG and UPG, between PB and RP specimen; however, it has no significant effect on complete preoperative understaging. The bigger pathological experience improves the sensitivity of the histological diagnostic process.

Sonochemical degradation of cyclic nitroxides in aqueous solution.

The sonochemical degradation of eight five- and six-membered nitroxides has been studied by EPR spectroscopy after exposure to ultrasound at a frequency of 354 kHz in argon-saturated aqueous solution. Concentration vs. time profiles do not follow a simple rate law. Octanol/water partition functions have been determined for all eight nitroxides, and an excellent linear correlation has been found between initial decomposition rates and hydrophobicity (log K(octanol/water)). Variation of initial rate with concentration was investigated for one compound (TEMPONE) and is largely consistent with an equilibrium distribution of substrate between bulk solution and the gas/liquid interface.

Claudins and ki-67: potential markers to differentiate low- and high-grade transitional cell carcinomas of the urinary bladder.

Updated classification of urothelial cell cancer differentiates low-grade and high-grade cancers, which determines potential clinical outcome. Substantial interobserver variability necessitates new biomarkers to ensure classification. Claudins' specific expression pattern characterizes normal tissues, different tumor types, and defined grades of tumor differentiation. The aim of this study was to examine the expression pattern of claudins and proliferation marker Ki-67 in low-grade and high-grade urothelial cell cancers compared with independent control samples of non-tumorous urothelium, as well as to reveal the predictive usefulness of claudins. The expression of claudins-1, -2, -3, -4, -5, -7, and -10 and Ki-67 was studied with quantitative immunohistochemistry and real-time RT-PCR with relative quantification in 103 samples: 86 urothelial cell cancers (27 low grade, 59 high grade) and 17 non-tumorous urothelia. Results were analyzed regarding overall survival and recurrence-free period as well. High-grade tumors overall showed significantly higher claudin-4 and Ki-67 and significantly lower claudin-7 expression when compared with low-grade ones. High-grade tumors revealed significantly shorter overall survival in Kaplan-Meier analysis. Claudin-4, claudin-7, and Ki-67 might be used as potential markers to differentiate low-grade and high-grade urothelial cell cancers, thereby possibly enhancing accuracy of pathological diagnosis and adding further information to clinical outcome.

Expression of claudins and their prognostic significance in noninvasive urothelial neoplasms of the human urinary bladder.

The members of the claudin family are major integral transmembrane protein constituents of tight junctions. Normal and neoplastic tissues can be characterized by unique qualitative and quantitative distribution of claudin subtypes, which may be related to clinicopathological features. Differential diagnosis and prognosis of nonmuscle invasive tumor entities of urinary bladder epithelium are often challenging. The aim was to investigate the expression profile of claudins in inverted urothelial papillomas (IUPs), urothelial papillomas (UPs), papillary urothelial neoplasms of low malignant potential (PUNLMPs), and intraepithelial (Ta), low-grade urothelial cell carcinomas (LG-UCCs) in order to reveal potential prognostic and differential diagnostic values of certain claudins. Claudin-1, -2, -4, and -7 protein expressions detected by immunohistochemistry and clinical data were analyzed in 15 IUPs, 20 UPs, 20 PUNLMPs, and 20 LG-UCCs. UPs, PUNLMPs, and LG-UCCs showed significantly decreased claudin-1 expression in comparison to IUPs. LG-UCCs expressing claudin-4 over the median were associated with significantly shorter recurrence-free survival. PUNLMPs expressing claudin-1 over the median revealed significantly longer recurrence-free survival. High claudin-1 protein expression might help to differentiate IUP from UPs, PUNLMPs, and LG-UCCs. High claudin-4 expression may determine an unfavorable clinical course of LG-UCCs, while high claudin-1 expression in PUNLMP was associated with markedly better clinical outcome.

Urinary matrix metalloproteinase-7 level is associated with the presence of metastasis in bladder cancer.

OBJECTIVE: • To assess the presence of matrix metalloproteinase (MMP)-7 in urine samples of patients with bladder cancer and to investigate the correlation between MMP-7 urine concentration and clinicopathological variables. PATIENTS AND METHODS: • The presence of MMP-7 in the urine of patients with bladder cancer was tested in 32 representative cases using immunoprecipitation followed by western blot analysis. • Urinary MMP-7 concentration levels were analyzed in 132 patients with bladder cancer and 96 controls using an enzyme-linked immunosorbent assay. RESULTS: • MMP-7 levels did not differ significantly between patients with localized bladder cancer and controls (P= 0.174). On the other hand, we detected a fourfold, significantly elevated MMP-7 concentration in urine samples of patients with bladder cancer with regional or distant metastasis (P= 0.003). • Using a threshold value of 6.88 ng/ml, determined by receiver-operating characteristic curve analysis, a specificity of 82% and a sensitivity of 78% were observed. • Western blot analysis revealed that the 55-kDa tissue inhibitor of metalloproteinase 1 complexed MMP-7 is the dominant form of urinary matrilysin. CONCLUSIONS: • MMP-7 is present in detectable amounts in the urine of patients with bladder cancer. Its concentrations are significantly elevated in patients with metastatic disease. • Determination of urinary matrilysin level could help to detect bladder cancer metastasis, and may therefore provide a more reliable prognosis and influence therapy decisions.

[Bilateral testicular tumor in a young man with congenital 11ß-hydroxylase deficiency]. / 11-ß-hidroxiláz enzim defektusában szenvedo fiatal férfi kétoldali heredaganata.

Adrenal rest tumor presenting as palpable testicular mass has been well described in boys and adult males with congenital adrenal hyperplasia. It develops most commonly in patients with 21- hydroxylase deficiency, but the entity may also occur in rare forms of congenital adrenal hyperplasia, including 11ß-hydroxylase deficiency. Because the management of testicular adrenal rest tumors is substantially different from that applied in benign and malignant testicular tumors, an accurate differentiation between these entities is particularly important. Authors present the history of a young adult male with 11ß-hydroxylase deficiency who developed adrenal rest tumors presenting as palpable bilateral testicular masses during treatment with glucocorticoids, then testicular masses showed a rapid regression after an adequate glucocorticoid treatment. Considering lessons obtained from this case, authors review the pathomechanism, symptoms, as well as current diagnostic and treatment modalities of testicular adrenal rest tumors.