Prostate cancer associated 3 (PCA3) and TMPRSS2:ERG fusion (T:E) are established urinary RNA biomarkers for detecting clinically significant prostate cancer (csPCa, Grade Group ≥ 2). Large within-subject paired studies directly comparing post-DRE and non-DRE urine collection are lacking. Using a multicenter cohort with samples collected from the same patients, we evaluated the effect of urine collection method on PCA3 and T: E diagnostic performance. In a multicenter prospective study paired post-DRE and non-DRE whole-urine samples were collected before systematic biopsy. PCA3, T:E, and reference PSA RNAs were quantified in 373 post-DRE and 355 non-DRE eligible specimens. Logistic regression models combining PCA3, T:E, PSA density, and age were developed for post-DRE (PD2) and non-DRE (ND2) cohorts and evaluated by cross-validated receiver operating characteristic (ROC) analysis and decision curve analysis. PD2 outperformed ND2 in discrimination (AUC 0.78 versus 0.73) and net benefit. At 95

Urothelial carcinoma, predominantly appearing as non-muscle-invasive papillary urothelial carcinoma (NMIPUC), exhibits wide clinical variability. Accurate pathological staging and grading are essential for effective risk stratification and treatment decisions. Advancements in artificial intelligence (AI) open new opportunities to improve predictive models; however, their generalizability across diverse datasets remains to be addressed. This study developed a federated learning (FL)-based AI framework to enhance model robustness across institutions and predictive accuracy for non-muscle-invasive bladder cancer staging, grading, and a novel histological risk factor derived by clustering histological features for relapse prediction. Retrospective data, including 1437 NMIPUC cases from two institutions in Lithuania and Taiwan, were used for development and analysis. The FL models demonstrated improved robustness across participating institutions and higher accuracy compared to single-site models, achieving 86.2% accuracy for tumor stage and 79.2% for tumor grade, with minor performance variability across the datasets. Moreover, the novel histological risk factor outperformed conventional indicators of relapse-free survival (RFS) in NMIPUC patients treated with BCG immunotherapy, achieving hazard ratios of 2.7 (p = 0.0018) and 2.8 (p = 0.0208) in the Lithuania and Taiwan datasets, respectively. These findings highlight the potential of FL and histological feature-based AI models in providing robust, generalizable solutions for NMIPUC risk stratification and offer insights for personalized clinical interventions.

OBJECTIVES:Clear cell renal cell carcinoma (ccRCC) is a heterogeneous tumor that may progress after nephrectomy as local or distant disease. The ccRCC tumor microenvironment (TME) hinges on two complementary pillars of immune response and angiogenesis. We aimed to assess if spatial CD8 and CD34 profiles at the tumor-stroma interface predict progression-free survival (PFS). METHODS:We retrospectively analyzed 214 ccRCC patients treated at Vilnius University Hospital Santaros Klinikos (2009 - 2019). Immunohistochemistry for CD8 and CD34 was performed on surgical tumor excision samples, and digital image analysis was performed to quantify cell densities and vessel areas relative to their spatial patterns within the tumor-stroma interface. The impact on PFS of CD8+ immunogradient and CD34+ area fraction was tested. RESULTS:Two prognostic models were developed: a Baseline model using variables available after surgery and a Disease-Course model additionally incorporating follow-up information. In the Baseline model, higher CD8_m_CM independently predicted shorter PFS (HR 3.24, p = 0.001), together with tumor size >4.95 cm and coagulative tumor necrosis, while female sex predicted longer PFS. In the Disease-Course model, local recurrence was the strongest adverse predictor (HR 17.69, p < 0.001), while both spatial biomarkers remained independently associated with PFS: higher CD8_m_CM predicted shorter PFS (HR 5.14, p = 0.001), whereas higher VAF_m_CM predicted longer PFS (HR 0.32, p = 0.014). CONCLUSIONS:Spatial patterns of immune and vascular components at the tumor-stroma interface independently predict PFS in patients with ccRCC following nephrectomy and may improve current risk stratification schemes in both the immediate postoperative setting and during follow-up.

The limited reproducibility of the grading of non-muscle invasive papillary urothelial carcinoma (NMIPUC) necessitates the search for more robust image-based predictive factors. In a cohort of 157 NMIPUC patients treated with Bacille Calmette–Guérin (BCG) immunotherapy, we explored the multiple instance learning (MIL)-based classification approach for the prediction of 2-year and 5-year relapse-free survival and the multiple instance survival learning (MISL) framework for survival regression. We used features extracted from image patches sampled from whole slide images of hematoxylin–eosin-stained transurethral resection (TUR) NPMIPUC specimens and tested several patch sampling and feature extraction network variations to optimize the model performance. We selected the model showing the best patient survival stratification for further testing in the context of clinical and pathological variables. MISL with the multiresolution patch sampling technique achieved the best patient risk stratification (concordance index = 0.574, p = 0.010), followed by a 2-year MIL classification. The best-selected model revealed an independent prognostic value in the context of other clinical and pathologic variables (tumor stage, grade, and presence of tumor on the repeated TUR) with statistically significant patient risk stratification. Our findings suggest that MISL-based predictions can improve NMIPUC patient risk stratification, while validation studies are needed to test the generalizability of our models.

Non-muscle-invasive papillary urothelial carcinoma (NMIPUC) of the urinary bladder is the most common type of bladder cancer. Intravesical Bacille Calmette–Guerin (BCG) immunotherapy is applied in patients with a high risk of recurrence and progression of NMIPUC to muscle-invasive disease. However, the tumor relapses in about 30% of patients despite the treatment, raising the need for better risk stratification. We explored the potential of spatial distributions of immune cell subtypes (CD20, CD11c, CD163, ICOS, and CD8) within the tumor microenvironment to predict NMIPUC recurrence following BCG immunotherapy. Based on analyses of digital whole-slide images, we assessed the densities of the immune cells in the epithelial–stromal interface zone compartments and their distribution, represented by an epithelial–stromal interface density ratio (IDR). While the densities of any cell type did not predict recurrence, a higher IDR of CD11c (HR: 0.0012, p-value = 0.0002), CD8 (HR: 0.0379, p-value = 0.005), and ICOS (HR: 0.0768, p-value = 0.0388) was associated with longer recurrence-free survival (RFS) based on the univariate Cox regression. The history of positive repeated TUR (re-TUR) (HR: 4.93, p-value = 0.0001) and T1 tumor stage (HR: 2.04, p-value = 0.0159) were associated with shorter RFS, while G3 tumor grade according to the 1973 WHO classification showed borderline significance (HR: 1.83, p-value = 0.0522). In a multivariate analysis, the two models with a concordance index exceeding 0.7 included the CD11c IDR in combination with either a history of positive re-TUR or tumor stage. We conclude that the CD11c IDR is the most informative predictor of NMIPUC recurrence after BCG immunotherapy. Our findings highlight the importance of assessment of the spatial distribution of immune cells in the tumor microenvironment.

Background and Objectives: Germline DNA damage response (DDR) gene mutations correlate with increased prostate cancer (PCa) risk and a more aggressive form of the disease. DDR mutation testing is recommended for metastatic PCa cases, while eligible information about the mutations’ burden in the early-stage localized PCa is still limited. This study is aimed at the prospective detection of DDR pathway mutations in cases with localized PCa and correlation with clinical, histopathological, and radiological data. A comparison to the previously assessed cohort of the advanced PCa was performed. Materials and Methods: Germline DDR gene mutations were assessed prospectively in DNA samples from 139 patients, using a five-gene panel (BRCA1, BRCA2, ATM, CHEK2, and NBN) targeted next-generation sequencing. Results: This study revealed an almost three-fold higher risk of localized PCa among mutation carriers as compared to non-carriers (OR 2.84 and 95% CI: 0.75–20.23, p = 0.16). The prevalence of germline DDR gene mutations in PCa cases was 16.8% (18/107) and they were detected only in cases with PI-RADS 4/5 lesions. BRCA1/BRCA2/ATM mutation carriers were 2.6 times more likely to have a higher (>1) cISUP grade group compared to those with a CHEK2 mutation (p = 0.27). However, the number of cISUP > 1-grade patients with a CHEK2 mutation was significantly higher in advanced PCa than in localized PCa: 66.67% vs. 23.08% (p = 0.047). Conclusions: The results of our study suggest the potential of genetic screening for selected DDR gene mutations for early identification of cases at risk of aggressive PCa.

2023 m. birželio mėn. Vilniaus universiteto ligoninėje Santaros klinikose pradėtos atlikti robotinės operacijos, naudojant robotinės chirurgijos sistemą „Versius“ (CMR, Kembridžas, JK). Per pirmąsias tris savaites atliktos 29 robotinės operacijos. Sistema įsigyta panaudojus Europos regioninės plėtros fondo lėšas. Išsamius 3 mėn. teorinius kursus išklausė ir praktiniuose mokymuose dalyvavo 32 Santaros klinikų medicinos darbuotojai. Jie suformavo 8 nepriklausomas komandas, sudarytas iš 2 chirurgų ir 2 slaugytojų. Mokymosi kursai apėmė: nuotolinius teorinio mokymo modulius; vienos savaitės mokymosi kursą, kurio metu lavinti techniniai įgūdžiai naudojant virtualiosios realybės simuliatorius; techninių įgūdžių mokymus, naudojant pilvo ertmės ir krūtinės ląstos ertmės operacijų muliažus; praktinius seminarus, per kuriuos buvo atliekamos operacijos, naudojant kadaverinius preparatus. Artėjant pirmosioms operacijoms, visos 8 komandos išėjo antrąjį mokymosi kursą operacinėje, naudodamiesi chirurginių įgūdžių lavinimo ir operacijų simuliavimo muliažais. Mokymų kursų pabaigoje atliktos kruopščiai suplanuotos pirmosios robotinės operacijos, dalyvaujant patyrusiems robotinės chirurgijos specialistams – mentoriams. Kruopštus standartizuotas mokymosi procesas leido greitai ir sklandžiai įdiegti robotinę chirurgiją į klinikinę praktiką, nekeliant pavojaus pacientams. Naudodami chirurginę sistemą „Versius“, pilvo chirurgai, urologai ir ginekologai jau atliko reikšmingą kiekį operacijų, išvengdami didelių komplikacijų. Pastaruoju metu pirmąsias operacijas atliko ir krūtinės chirurgai. Taip Vilniaus universiteto ligoninėje Santaros klinikose baigiamas robotinės chirurgijos sistemos „Versius“ daugiadisciplinio diegimo procesas. Straipsnio tikslas – pasidalyti pirmąja patirtimi, naudojant „Versius“ robotinės chirurgijos sistemą, ir įvertinti šios sistemos diegimo Vilniaus universiteto ligoninėje Santaros klinikose procesą.

(1) Background: DNA damage response (DDR) pathway gene mutations are detectable in a significant number of patients with metastatic castration-resistant prostate cancer (mCRPC). The study aimed at identification of germline and/or somatic DDR mutations in blood and urine samples from patients with mCRPC for correlation with responses to entire sequence of systemic treatment and survival outcomes. (2) Methods: DDR gene mutations were assessed prospectively in DNA samples from leukocytes and urine sediments from 149 mCRPC patients using five-gene panel targeted sequencing. The impact of DDR status on progression-free survival, as well as treatment-specific and overall survival, was evaluated using Kaplan–Meier curves and Cox regression. (3) Results: DDR mutations were detected in 16.6% of urine and 15.4% of blood samples. BRCA1, BRCA2, CHEK2, ATM and NBN mutations were associated with significantly shorter PFS in response to conventional androgen deprivation therapy and first-line mCRPC therapy with abiraterone acetate. Additionally, BRCA1 and BRCA2 mutation-bearing patients had a significantly worse response to radium-223. However, DDR mutation status was predictive for the favourable effect of second-line abiraterone acetate after previous taxane-based chemotherapy. (4) Conclusions: Our data confirm the benefit of non-invasive urine-based genetic testing for timely identification of high-risk prostate cancer cases for treatment personalization.

This study aimed to investigate the extent of field cancerization adjacent to index lesions in prostate cancer (PCa) by measuring DNA methylation of selected tumor suppressor genes in the perifocal tissue of PCa not visible on multiparametric magnetic resonanse imaging (mpMRI) for the safe zone of focal therapy identification.

Intraoperative hypotension (IOH) and loss of blood during radical nephrectomy (RN) cause postoperative clinically significant renal dysfunction, which after 12 months can cause a reduction in serum creatinine clearance of <60 mL/min. We conducted a prospective study of 93 adult patients in which we investigated the risk factors for developing chronic kidney disease (CKD) after RN. Forty-six (49.5%) patients had CKD, and of them, 43 patients had acute kidney injury (AKI) 48 h after surgery. Sixty-six (73.1%) of the postoperative AKI patients had CKD upstage. With each 1 mL estimated blood loss during RN (OR 1.01, p < 0.001), IOH was evaluated as the main risk factor of postoperative CKD development (OR 1.09, p < 0.01). Dunn’s t-test revealed that only clinically significant AKI had a main effect (g = −1.08, p < 0.0001) on renal function 1 year after RN. A higher preoperative estimated glomerular filtration rate (eGFR), OR 0.89, p = 0.02, and contralateral kidney CT volume (OR 0.97, p = 0.04) had a clinically significantly decreased risk of postoperative CKD. Risk factors of AKI with CKD upstage were a small contralateral kidney CT volume (OR 46.70), NLR > 3.5 (OR 1.42), higher primary eGFR (OR 1.13) and longer IOH (OR 1.05), and for all of these, p < 0.03. A half of all patients after RN are at increased risk of CKD. Longer IOH and increased blood loss during RN are significant risk factors for CKD. Clinically significant postoperative AKI is related with a developed risk for postoperative eGFR decline and the presence of CKD 12 months after RN, and can be predicted by NLR > 3.5. A higher preoperative eGFR and contralateral kidney CT volume reduces the risk of postoperative CKD.

Background and objectives: Teverelix drug product (DP) is a gonadotropin-releasing hormone antagonist in development for the treatment of patients with prostate cancer in whom androgen deprivation therapy is indicated. The aim of this paper is to present the results of five Phase 2 studies that assessed the pharmacokinetics, pharmacodynamics, efficacy and safety of different loading dose regimens of teverelix DP. Methods: Five single-arm, uncontrolled clinical trials were conducted in patients with advanced prostate cancer. The five different loading dose regimens of teverelix DP tested were (a) a single 90 mg subcutaneous (SC) injection of teverelix DP given on 3 consecutive days (Days 0, 1 and 2); (b) a single 90 mg intramuscular (IM) injection of teverelix DP given 7 days apart (Days 0 and 7); (c) a single 120 mg SC injection of teverelix DP given on 2 consecutive days (Days 0 and 1); (d) 2 × 60 mg SC injections of teverelix DP given on 3 consecutive days (Days 0, 1 and 2), and (e) 2 × 90 mg SC injections of teverelix DP given on 3 consecutive days (Days 0, 1 and 2). The primary efficacy parameter was the duration of action of an initial loading dose regimen in terms of suppression of testosterone to below the castration level (0.5 ng/mL). Results: Eighty-two patients were treated with teverelix DP. Two regimens (90 mg and 180 mg SC on 3 consecutive days) had a mean duration of castration of 55.32 days and 68.95 days with >90% of patients having testosterone levels < 0.5 ng/mL at Day 28. The mean onset of castration for the SC regimens ranged from 1.10 to 1.77 days, while it was slower (2.4 days) with IM administration. The most common adverse event (AE) was injection site reaction. No AEs of severe intensity were reported. Conclusions: Teverelix DP is safe and well tolerated. Castrate levels of testosterone can be rapidly achieved following the subcutaneous injection of teverelix DP on 3 consecutive days. Streamlining of the administration of the loading dose and identifying a suitable maintenance dose will be investigated in future trials.

Background: Bacille Calmette–Guerin (BCG) immunotherapy is the first-line treatment in patients with high-risk non-muscle invasive papillary urothelial carcinoma (NMIPUC), the most common type of bladder cancer. The therapy outcomes are variable and may depend on the immune response within the tumor microenvironment. In our study, we explored the prognostic value of CD8+ cell density gradient indicators across the tumor epithelium–stroma interface of NMIPUC. Methods: Clinical and pathologic data were retrospectively collected from 157 NMIPUC patients treated with BCG immunotherapy after transurethral resection. Whole-slide digital image analysis of CD8 immunohistochemistry slides was used for tissue segmentation, CD8+ cell quantification, and the assessment of CD8+ cell densities within the epithelium–stroma interface. Subsequently, the gradient indicators (center of mass and immunodrop) were computed to represent the density gradient across the interface. Results: By univariable analysis of the clinicopathologic factors, including the history of previous NMIPUC, poor tumor differentiation, and pT1 stage, were associated with shorter RFS (p < 0.05). In CD8+ analyses, only the gradient indicators but not the absolute CD8+ densities were predictive for RFS (p < 0.05). The best-performing cross-validated model included previous episodes of NMIPUC (HR = 4.4492, p = 0.0063), poor differentiation (HR = 2.3672, p = 0.0457), and immunodrop (HR = 5.5072, p = 0.0455). Conclusions: We found that gradient indicators of CD8+ cell densities across the tumor epithelium–stroma interface, along with routine clinical and pathology data, improve the prediction of RFS in NMIPUC.

The primary objective of this study was to demonstrate the high accuracy of multiparametric magnetic resonance imaging and ultrasound fusion (mpMRI/US)-guided targeted prostate biopsy for the detection of clinically significant prostate cancer (PCa) and to show that adapted systematic biopsy (AdSB) does not provide additional benefit in detecting clinically significant prostate cancer (PCa). In total, 283 patients have been included in the study. All patients underwent the mpMRI/US biopsies, which have been performed with the “BioJet” fusion system (D&K Technologies, Barum, Germany) using the transperineal approach by a single interventional radiologist. Lesion-targeted and systematic biopsies have been done when 2–4 cores have been taken from each PI-RADS 3–5 lesion, followed by AdSB. This study demonstrated that targeted prostate biopsy is sufficient for safe and sensitive identification of clinically significant PCa in primary biopsy-naïve cases without the need to perform adapted systematic biopsy.

Despite novel agents have been introduced to treat castration resistant prostate cancer (CRPC) during the last decade, up to one‐third of CRPC patients face primary resistance to new generation compounds. Therefore, sensitive molecular tools are urgently needed for reliable treatment selection and response prediction. This study aimed to evaluate urinary miRNAs and blood circulating androgen receptor (AR) transcript level as a tool for noninvasive outcome prediction for CRPC patients undergoing abiraterone acetate (AA) therapy.