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Toll-like receptor 3 (TLR3) is an endosomal receptor expressed in several immune and epithelial cells. Recent studies have highlighted its expression also in solid tumors, including prostate cancer (PCa), and have described its role primarily in the proinflammatory response and induction of apoptosis. It is up-regulated in some castration-resistant prostate cancers. However, the role of TLR3 in prostate cancer progression remains largely unknown. The current study experimentally demonstrated that exogenous TLR3 activation in PCa cell lines leads to a significant induction of secretion of the cytokines IL-6, IL-8, and interferon-β, depending on the model and chemoresistance status. Transcriptomic analysis of TLR3-overexpressing cells revealed a functional program that is enriched for genes involved in the regulation of cell motility, migration, and tumor invasiveness. Increased motility, migration, and invasion in TLR3-overexpressing cell line were confirmed by several in vitro assays and using an orthotopic prostate xenograft model in vivo. Furthermore, TLR3-ligand induced apoptosis via cleavage of caspase-3/7 and poly (ADP-ribose) polymerase, predominantly in TLR3-overexpressing cells. These results indicate that TLR3 may be involved in prostate cancer progression and metastasis; however, it might also represent an Achilles heel of PCa, which can be exploited for targeted therapy.

Background Partial nephrctomy (PN) has become the dominant treatment modality for cT1 renal tumor lesions. Tumors suspected of malignant potential are indicated for surgery, but some are histologically classified as benign lesions after surgery. This study aims to analyze the number of benign findings after PN according to definitive histology and to evaluate whether there is an association between malignant tumor findings and individual factors. Methods The retrospective study included 555 patients who underwent open or robotic-assisted PN for a tumor in our clinic from January 2013 to December 2020. The cohort was divided into groups according to definitive tumor histology (malignant tumors vs. benign lesions). The association of factors (age, sex, tumor size, R.E.N.A.L.) with the malignant potential of the tumor was further evaluated. Results In total, 462 tumors were malignant (83%) and 93 benign (17%). Of the malignant tumors, 66% were clear-cell RCC, 12% papillary RCC, and 6% chromophobe RCC. The most common benign tumor was oncocytoma in 10% of patients, angiomyolipoma in 2%, and papillary adenoma in 1%. In univariate analysis, there was a higher risk of malignant tumor in males (OR 2.13, 95% CI 1.36-3.36, p=0.001), a higher risk of malignancy in tumors larger than 20 mm (OR 2.32, 95% CI 1.43-3.74, pConclusions In this group, 17% of tumors had benign histology. Male sex, tumor size greater than 20 mm, and intermediate or high R.E.N.A.L. complexity were statistically significant predictors of malignant tumor findings.

High expression of the androgen receptor (AR) and the disruption of its regulation are strongly responsible for the development of prostate cancer (PCa). Therapeutically relevant non-steroidal or steroidal antiandrogens are able to block the AR effect by eliminating AR-mediated signalling. Herein we report the synthesis of novel steroidal pyrazoles derived from the natural sex hormone 5α-dihydrotestosterone (DHT). 2-Ethylidene or 2-(hetero)arylidene derivatives of DHT obtained by regioselective Claisen-Schmidt condensation with acetaldehyde or (hetero)aromatic aldehydes in alkaline ethanol were reacted with monosubstituted hydrazines to give A-ring-fused 1,5-disubstituted pyrazoles as main or exclusive products, depending on the reaction conditions applied. Spontaneous or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)-induced oxidation of the primarily formed pyrazolines resulted in the desired products in moderate to good yields, while 17-oxidation also occurred by using the Jones reagent as a strong oxidant. Transcriptional activity of the AR in a reporter cell line was examined for all novel compounds, and several previously synthesized similar DHT-based pyrazoles with differently substituted heteroring were also included to obtain information about the structure-activity relationship. Two specific regioisomeric groups of derivatives significantly diminished the transcriptional activity of AR in reporter cell line in 10 μM concentration, and displayed reasonable antiproliferative activity in AR-positive PCa cell lines. Lead compound (3d) was found to be a potent AR antagonist (IC50= 1.18 μM), generally suppressed AR signalling in time and dose dependent manner, moreover, it also led to a sharp decrease in wt-AR protein level probably caused by proteasomal degradation. We confirmed the antiproliferative activity selective for AR-positive PCa cell lines (with GI50in low micromolar ranges), cellular, biochemical and in silico binding of3din AR ligand-binding domain. Moreover, compound3dwas shown to be potent evenex vivoin patient-derived tissues, which highlights the therapeutic potential of A-ring-fused pyrazoles.Table of content graphicHighlightsA-ring-fused pyrazoles of 5α-dihydrotestosterone were introduced as AR modulatorsSAR study of 55 differently substituted derivatives was discussedCompound3dsuppressed the expression of AR targets in prostate cell linesCompound3dcaused AR degradation in time-dependent mannerEx vivo activity of3dwas demonstrated in patient-derived explants

Aims. With the introduction of magnetic resonance imaging in the diagnosis of prostate cancer and its use in targeted prostate biopsy, an increased incidence of anterior-predominant prostate cancer (APC) has been observed. Methods. We enrolled 200 patients who underwent radical prostatectomy at our department between 12/2017 and 04/2019. We evaluated tumour location in the individual segments of the prostate, index tumour location and volume, and compared the postoperative stage, Gleason score, grade group (GG), and the presence of extraprostatic extension (EPE) in APC and posterior prostate cancer (PPC). We assessed the rate of MRI scans prior to prostate surgery as well as the influence of family history and PSA on the presence of APC. Results. We found a significantly higher rate of anterior tumours than previously reported (37%) and confirmed that these tumours are diagnosed with a significantly larger index tumour volume (P=0.003). We also showed that a mere 6.76% of APCs were low-risk tumours not requiring radical treatment. Furthermore, anterior tumours were found significantly more often (P=0.001) in patients who underwent preoperative MRI. No differences were observed between PSA values, family history, presence of EPE, or locally advanced disease in APC vs. PPC. Conclusions. The frequency of anterior tumours is higher than previously thought, and they include tumours requiring radical treatment. When these tumours are neglected, it may lead to patient undertreatment with impact on their life prognosis. Thus, we consider the use of MRI-targeted prostate biopsy to be a necessity both for ruling out APC in the case of repeatedly negative prostate biopsies and, in particular, before patient inclusion in active surveillance.

Objective: To present a case of isolated fluidothorax as a symptom of atypical late ovarian hyperstimulation syndrome. Methods: Review of available information and presentation of our case observed at the Department of Obstetrics and Gynaecology, 1st Faculty of Medicine, Charles University and University Hospital Bulovka. GnRH antagonist protocol was used to stimulate the patient and fresh embryo transfer was performed. Sixteenth day after the oocyte retrieval the patient was examined due to dyspnoea and lab exam proved ovarian hyperstimulation syndrome. Conclusion: Late ovarian hyperstimulation syndrome can lead to isolated fl uidothorax in case of additional favourable conditions. Key words: hydrothorax – ovarian hyperstimulation syndrome

Objective Based on the SUCCOR study database, our primary objective was to identify the independent clinical pathological variables associated with the risk of relapse in patients with stage IB1 cervical cancer who underwent a radical hysterectomy. Our secondary goal was to design and validate a risk predictive index (RPI) for classifying patients depending on the risk of recurrence. Methods Overall, 1116 women were included from January 2013 to December 2014. We randomly divided our sample into two cohorts: discovery and validation cohorts. The test group was used to identify the independent variables associated with relapse, and with these variables, we designed our RPI. The index was applied to calculate a relapse risk score for each participant in the validation group. Results A previous cone biopsy was the most significant independent variable that lowered the rate of relapse (odds ratio [OR] 0.31, 95% confidence interval [CI] 0.17–0.60). Additionally, patients with a tumor diameter >2 cm on preoperative imaging assessment (OR 2.15, 95% CI 1.33–3.5) and operated by the minimally invasive approach (OR 1.61, 95% CI 1.00–2.57) were more likely to have a recurrence. Based on these findings, patients in the validation cohort were classified according to the RPI of low, medium, or high risk of relapse, with rates of 3.4%, 9.8%, and 21.3% observed in each group, respectively. With a median follow-up of 58 months, the 5-year disease-free survival rates were 97.2% for the low-risk group, 88.0% for the medium-risk group, and 80.5% for the high-risk group (p < 0.001). Conclusion Previous conization to radical hysterectomy was the most powerful protective variable of relapse. Our risk predictor index was validated to identify patients at risk of recurrence.

Karnozin (β-alanyl-L-histidin) je dipeptid, tvořený aminokyselinou β-alaninem a L-histidinem. Karnozin a obě aminokyseliny se vyskytuji v mozku a kosternim svalstvu vsech obratlovců. Karnozin v buňkach mozkove tkaně chrani intracelularni bilkoviny před jejich poskozenim kyslikovými radikaly, glykaci a tvorbou přicných vazeb mezi jednotlivými řetězci bilkovin. V kosternim svalstvu karnozin snižuje svalovou unavu způsobenou zvýsenou koncentraci kyseliny mlecne, ktera vede k poklesu pH. S rostoucim biologickým věkem klesa koncentrace karnozinu jak v buňkach mozkove tkaně, tak v bilých svalových vlaknech kosterniho svalstva, cimž dochazi k zhorsovani senzorických a kognitivnich funkci a ubytku svaloviny. Tyto degenerativni procesy lze zpomalit konzumaci potravin bohatých na karnozin nebo doplňovanim diety β-alaninem. β-alanin urcuje rychlost tvorby karnozinu a jeho koncentraci v buňkach mozkove a svalove tkaně. Clanek shrnuje soucasne nazory mediciny na roli karnozinu v procesu starnuti lidskeho organismu a významu obohacovani diety β-alaninem.

In metastatic prostate cancer (mPCa), the standard treatment involves systemic treatment including androgen deprivation therapy (ADT), possibly in combination with new drugs called androgen receptor targeting agents (ARTA) or docetaxel. The treatment of the prostate itself in mPCa represents a new paradigm in the so-called oligometastatic prostate cancer (OMPCa), which is considered to be a kind of intermediate stage between localized disease and extensive metastatic disease. Thanks to new dia-gnostic methods, OMPCa is an increasingly frequently dia-gnosed stage of mPCa. In addition to improving local control of the disease, aggressive local therapy could lower the need for ADT, or improve survival. Radiotherapy has already demonstrated the oncological benefit of OMPCa in a randomized study and is now part of the guidelines for the treatment of low volume de novo mPCa. Cytoreductive prostatectomy (CP) is still awaiting the results of randomized trials; however, retrospective data already exist to support this treatment modality. Several population-based studies have been published that have demonstrated the benefit of CP. Minor retrospective works have demonstrated the safety of CP in clinical practice. Several prospective randomized trials investigating this treatment modality are currently underway. However, the whole concept of CP in OMPCa is still shrouded in many unresolved issues such as the definition of a suitable patient and the role of another form of local therapy targeted to metastases.This article aims to provide an overview of key published or ongoing studies related to CP in relation not only to functional and oncological results but also to the indication criteria and design of individual studies.

Purpose: RCC, the most common type of kidney cancer, is associated with high mortality. A non-invasive diagnostic test remains unavailable due to the lack of RCC-specific biomarkers in body fluids. We have previously described a significantly altered profile of sulfatides in RCC tumor tissues, motivating us to investigate whether these alterations are reflected in collectible body fluids and whether they can enable RCC detection. Methods: We collected and further analyzed 143 plasma, 100 urine, and 154 tissue samples from 155 kidney cancer patients, together with 207 plasma and 70 urine samples from 214 healthy controls. Results: For the first time, we show elevated concentrations of lactosylsulfatides and decreased levels of sulfatides with hydroxylated fatty acyls in body fluids of RCC patients compared to controls. These alterations are emphasized in patients with the advanced tumor stage. Classification models are able to distinguish between controls and patients with RCC. In the case of all plasma samples, the AUC for the testing set was 0.903 (0.844–0.954), while for urine samples it was 0.867 (0.763–0.953). The models are able to efficiently detect patients with early- and late-stage RCC based on plasma samples as well. The test set sensitivities were 80.6% and 90%, and AUC values were 0.899 (0.832–0.952) and 0.981 (0.956–0.998), respectively. Conclusion: Similar trends in body fluids and tissues indicate that RCC influences lipid metabolism, and highlight the potential of the studied lipids for minimally-invasive cancer detection, including patients with early tumor stages, as demonstrated by the predictive ability of the applied classification models.

Prezentujeme připad 72leteho muže s leiomyosarkomem funikulus spermaticus. Pacient byl vysetřen pro bolesti praveho třisla a zvětseni praveho hemiskrota. Fyzikalni vysetřeni prokazalo tuhou masu, ktera zasahovala až do dolni poloviny třiselneho kanalu. Ultrazvukove vysetřeni zjistilo solidni expanzi s heterogenni strukturou a akcentovanou vaskularizaci. Byla provedena radikalni orchiektomie s vysokou ligaci funiculu. Histologicky byl verifikovan nizce diferencovaný leiomyosarkom funikulus spermaticus, nador patřici do skupiny paratestikularnich tumorů. Stagingove CT plic, retroperitonea a male panve neodhalilo postiženi lymfatik ci vzdalene metastazy. Pooperacně nebyla po zvaženi na multioborovem seminaři indikovana adjuvantni onkologicka terapie. Důvodem byla zejmena radikalita chirurgickeho výkonu. Během dispenzarizace byl po třech letech zjistěn metastatický proces v retroperitonealnich uzlinach.

BackgroundDocetaxel resistance represents a leading obstacle in the therapy of prostate cancer (PCa), resulting in lethal disease. Intratumoral heterogeneity, which is frequently driven by epithelial-mesenchymal plasticity significantly contributes to the limited treatment response, chemoresistance, and subsequent poor prognosis of patients with lethal PCa.MethodsWe employed a high-throughput flow cytometry screening to identify cell surface fingerprint that associates with docetaxel resistance in PCa cells. Using patient-derived xenografts, we validated protein expression of the most robustly changed antigens in vivo and further assessed this 6-molecule surface fingerprint in primary PCa tumors.ResultsWe revealed the overexpression of SSEA-4 antigen in both in vitro and in vivo docetaxel-resistant models and confirmed the SSEA-4 enrichment in a subpopulation of freshly isolated primary PCa tumors. The level of ST3GAL2, an enzyme that is critically involved in the SSEA-4 synthesis, correlated with increased expression of CD44, CD59, and CD95 and reduced expression of EpCAM and CD9. SSEA-4 was further directly linked to the antimicrotubule agent resistance and poor prognosis in PCa patients.ConclusionsWe propose that the 6-molecule surface fingerprint associates with docetaxel resistance and pre-exists in a cell subpopulation of primary PCa tumors even before docetaxel treatment.

Karcinom prostaty je v soucasne době třetim nejcastějsim onkologickým onemocněnim u mužů v CR a druhým nejcastěji se vyskytujicim nadorem u mužů v celosvětovem měřitku. Jeho incidence každým rokem stoupa. Každým rokem jsou aktualizovany diagnosticko-terapeuticke algoritmy lecby karcinomu prostaty, ktere zohledňuji miru lokalni progrese tumoru, jeho stupeň histologicke diferenciace a miru metastatickeho rozsevu. V připadě karcinomu prostaty býva nejcastějsim mistem vzdalených metastaz samotný skelet ci skelet v kombinaci s metastatickým postiženim ilických připadně paraaortalnich uzlin. V literatuře bylo zatim popsano jen velmi male množstvi plicnich metastaz karcinomu prostaty, ktere se navic větsinou vyskytovaly synchronně s kostnimi metastazami. Jejich výskyt navic koreloval s agresivnim histologickým subtypem tumoru (Gleason score 8 a vic) a elevaci PSA. Tento připad je raritni skutecnosti, že byla nalezena solitarni plicni metastaza karcinomu prostaty u pacienta s neměřitelnými hodnotami PSA a Gleason score 6 s vyloucenim generalizace do jiných mist.