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Abstract Background The tumoricidal complex alpha1‐oleate targets bladder cancer cells, triggering rapid, apoptosis‐like tumor cell death. Clinical effects of alpha1‐oleate were recently observed in patients with non‐muscle invasive bladder cancer (NMIBC), using a randomized, placebo‐controlled study protocol. Aims To investigate if there are dose‐dependent effects of alpha1‐oleate. Materials and Methods Here, patients with NMIBC were treated by intravesical instillation of increasing concentrations of alpha1‐oleate (1.7, 8.5, or 17 mM) and the treatment response was defined relative to a placebo group. Results Strong, dose‐dependent anti‐tumor effects were detected in alpha1‐oleate treated patients for a combination of molecular and clinical indicators; a complete or partial response was detected in 88% of tumors treated with 8.5 mM compared to 47% of tumors treated with 1.7 mM of alpha1‐oleate. Uptake of alpha1‐oleate by the tumor triggered rapid shedding of tumor cells into the urine and cell death by an apoptosis‐like mechanism. RNA sequencing of tissue biopsies confirmed the activation of apoptotic cell death and strong inhibition of cancer gene networks, including bladder cancer related genes. Drug‐related side effects were not recorded, except for local irritation at the site of instillation. Discussion and Conclusions These dose‐dependent anti‐tumor effects of alpha1‐oleate are promising and support the potential of alpha1‐oleate treatment in patients with NMIBC.

Abstract Background The molecular content of urine is defined by filtration in the kidneys and by local release from tissues lining the urinary tract. Pathological processes and different therapies change the molecular composition of urine and a variety of markers have been analyzed in patients with bladder cancer. The response to BCG immunotherapy and chemotherapy has been extensively studied and elevated urine concentrations of IL‐1RA, IFN‐α, IFN‐γ TNF‐α, and IL‐17 have been associated with improved outcome. Methods In this study, the host response to intravesical alpha 1‐oleate treatment was characterized in patients with non‐muscle invasive bladder cancer by proteomic and transcriptomic analysis. Results Proteomic profiling detected a significant increase in multiple cytokines in the treatment group compared to placebo. The innate immune response was strongly activated, including IL‐1RA and pro‐inflammatory cytokines in the IL‐1 family (IL‐1α, IL‐1β, IL‐33), chemokines (MIP‐1α, IL‐8), and interferons (IFN‐α2, IFN‐γ). Adaptive immune mediators included IL‐12, Granzyme B, CD40, PD‐L1, and IL‐17D, suggesting broad effects of alpha 1‐oleate treatment on the tumor tissues. Conclusions The cytokine response profile in alpha 1‐oleate treated patients was similar to that reported in BCG treated patients, suggesting a significant overlap. A reduction in protein levels at the end of treatment coincided with inhibition of cancer‐related gene expression in tissue biopsies, consistent with a positive treatment effect. Thus, in addition to killing tumor cells and inducing cell detachment, alpha 1‐oleate is shown to activate a broad immune response with a protective potential.

Renal cell carcinoma (RCC) is a common malignancy frequently diagnosed at the metastatic stage. We performed a comprehensive analysis of the tumor immune microenvironment (TIME) in RCC patients, including the peritumoral tissue microenvironment, to characterize the phenotypic patterns and functional characteristics of infiltrating immune cells. T cells from various compartments (peripheral blood, tumor, peritumoral area, and adjacent healthy renal tissue) were assessed using flow cytometry and Luminex analyses, both before and after T cell-specific stimulation, to evaluate activation status and migratory potential. Our findings demonstrated that tumor-infiltrating lymphocytes (TILs) exhibited heightened cytokine production compared to peritumoral T cells (pTILs), acting as the primary source of cytotoxic markers (IFN-γ, granzyme B, and FasL). CD8+ T cells primarily employed Fas Ligand for cytotoxicity, while CD4+ T cells relied on CD107a. In addition, a statistically significant negative correlation between patient mortality and the presence of CD4+CD107+ pTILs was demonstrated. The engagement with the PD-1/PD-L1 pathway was also more evident in CD4+ and CD8+ pTILs as opposed to TILs. PD-L1 expression in the non-leukocyte fraction of the tumor tissue was relatively lower than in their leukocytic counterparts and upon stimulation, peripheral blood T cells displayed much stronger responses to stimulation than TILs and pTILs. Our results suggest that tumor and peritumoral T cells exhibit limited responsiveness to additional activation signals, while peripheral T cells retain their capacity to respond to stimulatory signals

An updated Council of the EU recommendation on cancer screening was adopted in December 2022 during the Czech EU presidency. The recommendation included prostate cancer as a suitable target disease for organised screening, and invited countries to proceed with piloting and further research. To support further discussions and actions to promote early detection of prostate cancer, an international conference in November 2022 (Prostaforum 2022) resulted in a joint declaration. Here we describe the EU policy background, summarise the preparation of the declaration and the key underlying evidence and expert recommendations, and report the text of the declaration. The declaration summarises the striking inequalities in prostate cancer burden in Europe and calls on all stakeholders to consider and support concrete steps for advancement of organised early detection of prostate cancer. Our aim is to request endorsement of the text and potential initiation of practical actions by all stakeholders to support the aims of the declaration. Patient summary: Prostate cancer is among the most frequent cancers and is one of the most common causes of cancer death among men. The European Union has recommended new pilot programmes for prostate cancer screening. The Prostaforum 2022 declaration invites all stakeholders to support this new recommendation with specific steps.

Background: Radical cystectomy (RC) is indicated in primary or secondary muscle-invasive bladder cancer (primMIBC, secMIBC) and in primary or recurrent high- or very high-risk non–muscle-invasive bladder cancer (primHR-NMIBC, recHR-NMIBC). The optimal timing for RC along the disease spectrum of nonmetastatic urothelial carcinoma remains unclear. Objective: To compare outcomes after RC between patients with primHR-NMIBC, recHR-NMIBC, primMIBC, and secMIBC. Design, setting, and participants: This retrospective, multicenter study included patients with clinically nonmetastatic bladder cancer (BC) treated with RC. Outcome measurements and statistical analysis: We assessed oncological outcomes for patients who underwent RC according to the natural history of their BC. primHR-NMIBC and primMIBC were defined as no prior history of BC, and recHR-NMIBC and secMIBC as previously treated NMIBC that recurred or progressed to MIBC, respectively. Log-rank analysis was used to compare survival outcomes, and univariable and multivariable Cox and logistic regression analyses were used to identify predictors for survival. Results and limitations: Among the 908 patients included, 211 (23%) had primHR-NMIBC, 125 (14%) had recHR-NMIBC, 404 (44%) had primMIBC, and 168 (19%) had secMIBC. Lymph node involvement and pathological upstaging were more frequent in the secMIBC group than in the other groups (p

Background and Aim: Placental Growth Factor (PlGF) plays a crucial role in angiogenesis and was identified as a potential prognostic biomarker in various types of cancer. Therefore, we evaluated the diagnostic accuracy and prognostic value of PlGF serum concentration in patients with clear cell renal cell carcinoma (ccRCC). Patients and Methods: A total of 49 patients subjected to partial or radical nephrectomy for ccRCC [localized without relapse (lccRCC; n=31), localized with later relapse (rccRCC; n=8), primary metastatic cancer (mccRCC; n=10); median of follow-up 4.4 years] were enrolled in a prospective study to assess the significance of PlGF serum concentration. PlGF was measured prior to surgery and 3 months postoperatively. Our control group consisted of 38 healthy subjects. Results: PlGF serum concentration was significantly higher in ccRCC compared to controls (P=0.002). The cut-off value of PlGF concentration for the risk of ccRCC was determined at 12.71 pg/mL (AUC=0.729; P=0.0001). Prior to surgery, among ccRCC subgroups, significantly higher PlGF concentration was detected in mccRCC compared to lccRCC (P=0.002). Postoperatively, we observed a tendency to higher PlGF serum concentration in rccRCC compared to lccRCC subgroup, however without significance (P=0.17). The cut-off value for the risk of relapse was 11.41 pg/mL (AUC=0.792; P=0.0003). In subjects with localized ccRCC with PlGF concentration below 11.41 pg/mL 3-years cancer specific survival was 93% compared to 61% in subject with concentration above the cut-off value (P=0.018). Conclusion: Based on our findings, PlGF serum concentration seems to be a useful biomarker in diagnostics and prediction of prognosis in ccRCC.

Background. Cancer stem cells (CSC) and their role in tumorigenesis of various solid tumors have been studied in past decades. Urothelial CSC were first identified 10 years ago and subsequent studies have been performed with the aim to identify reliable markers of CSC. So far, a few studies have investigated a relationship between CSC markers expression in urothelial carcinoma tissue and histopathological characteristics of the tumor. Methods. In our study, we evaluated an immunoexpression of the CSC markers CD24, CD44, CD66 and CD133 in tissue sections of urothelial carcinoma (all tumor grades and stages were included), urothelial carcinoma in situ and non-neoplastic urothelium, totally 218 specimens were enrolled. Results. All studied molecules were expressed either in tumor tissue and non-neoplastic urothelium. Urothelial carcinomas of higher tumor grade and stage expressed molecules CD24 and CD133 significantly more frequently whereas molecules CD44 and CD66 did not show significant association with tumor histopathological features. Conclusions. Our results showed that studied molecules are not suitable for direct detection of CSC in urothelial carcinoma tissue sections, but an expression of molecules CD24 and CD133 is significantly related to urothelial carcinoma grade and stage, which are both important prognostic indicators and therefore an expression of these markers might have a potential prognostic value.

Partially unfolded alpha-lactalbumin forms an oleic acid complex with antitumorigenic properties. Here, the authors define a structurally flexible, peptide-based oleate complex and report a phase I/II clinical trial where this complex is used to treat patients with bladder cancer.

Background: Software-based MRI/TRUS fusion biopsy depends on the coordination of several steps, and inter-examiner differences could influence the results. The aim of this bicentric prospective study was to compare the detection rates of MRI/TRUS fusion targeted biopsy (TG) and systematic biopsy (SB), and the detection rates of examiners with different levels of previous experience in prostate biopsy. Methods: A total of 419 patients underwent MRI based on a suspicion of prostate cancer with elevated PSA levels. MRI was positive in 395 patients (221 in the first biopsy group [FB] and 174 in the repeated biopsy group [RB]). A subsequent TG, followed by a SB, was performed on these patients by four different examiners. Results: In the detection of clinically significant prostate cancer, a significant difference was found for TG+SB against SB in the RB group (35.1% vs. 25.3%, P=0.047). In the detection of clinically insignificant prostate cancer, the SB had a significantly higher detection rate than TG in both subgroups (FB: 11.9% vs. 4.7%, P=0.008; RB: 13.8% vs. 6.9%, P=0.034). A significant difference was found between the four examiners in the FB for TG (P=0.028), SB (P=0.036), and TG+SB (P=0.017). Conclusion: MRI/TRUS TG in combination with SB had significantly higher detection rates than SB in the RB group only. Differences in detection rates between examiners were dependent on the level of previous experience with TRUS guided biopsy.

The protein-lipid complex alpha1-oleate, derived from HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells), is identified as a molecular entity with significant therapeutic potential. Structural characterization of the complex and results of a successful placebo-controlled clinical trial are presented.