PD-L1 expression in tumor and inflammatory cells is associated with favorable tumor features and favorable prognosis in muscle-invasive urothelial carcinoma of the bladder not treated by immune checkpoint inhibitors.

BACKGROUND: A high level of PD-L1 expression is the most relevant predictive parameter for response to immune checkpoint inhibitor (CPI) therapy in urinary bladder cancer. Existing data on the relationship between PD-L1 expression and the natural course of disease are controversial and sparse. METHODS: To expand our understanding of the relationship between PD-L1 expression and parameters of cancer aggressiveness, PD-L1 was analyzed on tissue microarrays containing 2710 urothelial bladder carcinomas including 512 patients with follow-up data who underwent radical cystectomy and follow-up therapies in the pre-immune checkpoint inhibitor therapy era. RESULTS: Tumor cell positivity in ≥10% of cells were seen in 513 (20%) and an immune cell positivity occurred in 872 (34%) of 2566 interpretable cancers. PD-L1 positivity in tumor cells increased from pTaG2 low grade (0.9% positive) to pTaG3 high grade (4.1%; p = 0.0255) and was even higher in muscle-invasive (pT2-4) carcinomas (29.3%; p < 0.0001). However, within pT2-4 carcinomas, PD-L1 positivity was linked to low pT stage (p = 0.0028), pN0 (p < 0.0001), L0 status (p = 0.0005), and a better prognosis within 512 patients with cystectomy who never received CPIs (p = 0.0073 for tumor cells and p = 0.0086 for inflammatory cells). PD-L1 staining in inflammatory cells was significantly linked to PD-L1 staining in tumor cells (p < 0.0001) and both were linked to a positive p53 immunostaining (p < 0.0001). CONCLUSION: It cannot be fully excluded that the strong statistical link between PD-L1 status and favorable histological tumor features as well as better prognosis could influence the outcome of studies evaluating CPIs in muscle-invasive urothelial carcinoma.

Cytokeratin 20 expression is linked to stage progression and to poor prognosis in advanced (pT4) urothelial carcinoma of the bladder.

Cytokeratin 20 (CK20) expression is limited to umbrella cells in the normal urothelium. Since CK20 is often upregulated in neoplastic urothelial cells including dysplasia and carcinoma in situ, immunohistochemical CK20 analysis is often used for the assessment of bladder biopsies. CK20 expression is a feature of luminal bladder cancer subtype, but its prognostic relevance is disputed. In this study, we investigated CK20 on >2700 urothelial bladder carcinomas in a tissue microarray format by immunohistochemistry. Cytoplasmic and membranous CK20 staining was seen in 1319 (51.8%) cancers. The fraction of CK20 positive and especially strongly positive cases increased from pTaG2 low grade (44.5% strongly positive) and pTaG2 high grade (57.7%) to pTaG3 high grade (62.3%; p = 0.0006) but was lower in muscle-invasive (pT2-4) carcinomas (51.1% in all pTa vs. 29.6% in pT2-4; p < 0.0001). Within pT2-4 carcinomas, CK20 positivity was linked to nodal metastasis and lymphatic vessel invasion (p < 0.0001 each) and to venous invasion (p = 0.0177). CK20 staining was unrelated to overall patient survival if all 605 pT2-4 carcinomas were jointly analyzed but subgroup analyses revealed a significant association of CK20 positivity with favorable prognosis in 129 pT4 carcinomas (p = 0.0005). CK20 positivity was strongly linked to the expression of GATA3 (p < 0.0001), another feature of luminal bladder cancer. The combined analysis of both parameters showed best prognosis for luminal A (CK20+/GATA3+, CK20+/GATA3-) and worst outcome for luminal B (CK20-/GATA3+) and basal/squamous (CK20-/GATA3-) in pT4 urothelial carcinomas (p = 0.0005). In summary, the results of our study demonstrate a complex role of CK20 expression in urothelial neoplasms including neoexpression in pTa tumors, a subsequent loss of CK20 expression in a subset of tumors progressing to muscle-invasion, and a stage dependent prognostic role in muscle-invasive cancers.

Altered p53/p16 expression is linked to urothelial carcinoma progression but largely unrelated to prognosis in muscle-invasive tumors.

BACKGROUND: Most inactivating p53 mutations result in a nuclear p53 accumulation - detectable by immunohistochemistry (IHC). p53 alterations leading to a complete lack of p53 protein and absence of immunostaining do also occur - not easily detectable by IHC. p16 is upregulated in p53 inactivated cells. We hypothesized that a positive p16 IHC may help to distinguish p53 inactivation in IHC negative cases. MATERIAL AND METHODS: We investigated p53 and p16 immunostaining on 2710 urothelial bladder carcinomas in a tissue microarray format to understand their impact in relation to clinicopathological parameters of disease progression and patient outcome. RESULTS: p16 immunostaining was absent in normal urothelium but occurred in 63.5% (30.4% strong) of cancers. p16 strongly positive cases increased from pTaG2 low-grade (9.6%) to pTaG3 high-grade tumors (46.5%, p < .0001) but decreased from pTaG3 to pT4 (33.3%; p = .0030). Among pT2-4 carcinomas, p16 positivity was linked to high-grade (p = .0005) but unrelated to overall survival. p53 staining was negative in 8.4%, very weak in 15.4%, weak in 55.3%, strong in 4.7%, and very strong in 16.2% cancers. p53 negative (potentially p53 null phenotype), strong, and very strong p53 positivity increased from pTaG2 low-grade to pTaG3 high-grade tumors (p < .0001) and from pTaG3 to pT2-4 cancers (p = .0007). p53 staining was largely unrelated to histopathological parameters or patient prognosis among pT2-4 carcinomas, except of p53 strong/very strong immunostaining. p16 expression predominated in tumors with very strong, strong, and negative p53 staining and the combination of p53 negative/p16 strongly positive cancers was linked to features of tumor aggressiveness. CONCLUSION: Aberrant p53 and p16 immunostaining increases during grade and stage progression although p53 negative and p16 positive immunostaining lack prognostic significance in pT2-4 carcinomas. Potential diagnostic features are that high level p16 expression is limited to neoplastic urothelium and p53 null phenotype to aggressive cancers (grade 3 and invasive).

Recurrent PALB2 mutations and the risk of cancers of bladder or kidney in Polish population.

INTRODUCTION: The role of PALB2 in carcinogenesis remains to be clarified. Our main goal was to determine the prevalence of PALB2 (509_510delGA and 172_175delTTGT) mutations in bladder and kidney cancer patients from Polish population. MATERIALS AND METHODS: 1413 patients with bladder and 810 cases with kidney cancer and 4702 controls were genotyped for two PALB2 variants: 509_510delGA and 172_175delTTGT. RESULTS: Two mutations of PALB2 gene were detected in 5 of 1413 (0.35%) unselected bladder cases and in 10 of 4702 controls (odds ratio [OR], 1.7; 95% CI 0.56-4.88; p = 0.52). Among 810 unselected kidney cancer cases two PALB2 mutations were reported in two patients (0,24%) (odds ratio [OR], (OR = 1.2; 95% CI 0.25-5.13; p = 0.84). In cases with mutations in PALB2 gene cancer family history was negative. CONCLUSION: We found no difference in the prevalence of recurrent PALB2 mutations between cases and healthy controls. The mutations in PALB2 gene seem not to play a major role in bladder and kidney cancer development in Polish patients.

Percutaneous Nephrolithotomy Using an Individual 3-Dimensionally Printed Surgical Guide.

Percutaneous nephrolithotomy (PNL) is an endoscopic technique used for treating large stones, multiple stones, and staghorn calculi. Although minimally invasive, complication rate of PNL reaches 25%, and it is partially associated with needle puncture during nephrostomy tract preparation. Continuous improvement of armamentarium and imaging methods and the introduction of three-dimensional (3D) visualizations optimize the procedure; however, the rapid and precise establishment of the nephrostomy tract is still difficult. In the present short communication, we present the PNL procedure assisted by a personalized 3D-printed surgical guide (SG) to ensure fast and precise needle access to the renal collecting system. We also describe the workflow for SG preparation, which consists of CT image acquisition and data segmentation, planning a safe needle insertion path, SG designing, and guide manufacturing. With the growing market of low-cost 3D printers, the presented technique can shorten the PNL procedure time and decrease the complication rate associated with needle puncture in a cost-efficient manner.

Cadmium, lead and mercury concentrations in pathologically altered human kidneys.

Heavy metals, including cadmium (Cd), lead (Pb) and mercury (Hg) act as nephrotoxic agents, particularly in the renal cortex. The aim of the study was to determine the concentrations of Cd, Pb and Hg in kidneys removed from patients due to lesions of various etiologies and from patients after the rejection of transplanted kidneys. Additionally, we determined the influence of selected biological and environmental factors on the concentrations of toxic metals. The study material consisted of kidneys with tumor lesions (n = 27), without tumors (n = 7) and its extracted grafts (n = 10) obtained from patients belongs to the north-western areas of Poland. The determined metal concentrations in the renal cortex and medulla may be arranged in the following descending order: Cd > Pb > Hg. The highest concentrations of Cd and Hg were found in the cortex, while the maximum content Pb was observed in the medulla. Significant correlations were found in the concentrations of the same metals between cortex and medulla and between Pb and Hg in the renal medulla. Pb content was higher in the renal medulla of men than in the cortex of the elderly (above 60 years of age). The highest concentrations of Pb and Hg were found in the cortex and medulla, of the kidneys had not neoplastic changes, and lower content of these metals were found in the extracted kidney grafts. In summary, renal grafts accumulate less heavy metals than cancerous kidneys, what could have been caused by immunosuppressors taken by the graft recipients. Moreover, sex, age and smoking are key factors responsible for xenobiotics concentrations.

Three-Dimensional Printing as an Interdisciplinary Communication Tool: Preparing for Removal of a Giant Renal Tumor and Atrium Neoplastic Mass.

Three-dimensional (3D) printing involves preparing 3D objects from a digital model. These models can be used to plan and practice surgery. We used 3D printing to plan for a rare complicated surgery involving the removal of a renal tumor and neoplastic mass, which reached the heart atrium. A printed kidney model was an essential element of communication for physicians with different specializations.

The presence of prostate cancer at biopsy is predicted by a number of genetic variants.

Several single nucleotide polymorphisms (SNPs) have been associated with an elevated risk of prostate cancer risk. It is not established if they are useful in predicting the presence of prostate cancer at biopsy or if they can be used to define a low-risk group of men. In this study, 4,548 men underwent a prostate biopsy because of an elevated prostate specific antigen (PSA; ≥4 ng/mL) or an abnormal digital rectal examination (DRE). All men were genotyped for 11 selected SNPs. The effect of each SNP, alone and in combination, on prostate cancer prevalence was studied. Of 4,548 men: 1,834 (40.3%) were found to have cancer. A positive association with prostate cancer was seen for 5 of 11 SNPs studied (rs1800629, rs1859962, rs1447295, rs4430796, rs11228565). The cancer detection rate rose with the number of SNP risk alleles from 29% for men with no variant to 63% for men who carried seven or more risk alleles (OR = 4.2; p = 0.002). The SNP data did not improve the predictive power of clinical factors (age, PSA and DRE) for detecting prostate cancer (AUC: 0.726 vs. 0.735; p = 0.4). We were unable to define a group of men with a sufficiently low prevalence of prostate cancer that a biopsy might have been avoided. In conclusion, our data do not support the routine use of SNP polymorphisms as an adjunct test to be used on the context of prostate biopsy for Polish men with an abnormal screening test.

Assessment of the incidence and risk factors of postoperative urosepsis in patients undergoing ureteroscopic lithotripsy.

Introduction: Ureteroscopic lithotripsy (URSL) is an approved, minimally invasive, low-risk procedure for urolithiasis treatment. However, some patients may develop urinary tract infection (UTI) post-procedure, eventually leading to urosepsis. Determining the predictors of infection after URSL would help identify patients at a high risk of urosepsis, thereby enabling the early implementation of effective treatment. Therefore, we aimed to establish the incidence and predictors of urosepsis after URSL. Material and methods: We assessed 231 patients who underwent URSL using a holmium laser. The incidence of urosepsis during the 30-day post-treatment period was analysed, and potential predictors of urosepsis, including patient characteristics and individual clinical factors, were examined. Results: Statistical analysis revealed that 16.88% of patients had a confirmed positive urine culture before the procedure. Post-procedure urosepsis occurred in 4.76% of patients. Univariable analysis revealed that 3 factors were significantly associated with the risk of postoperative urosepsis: double-J stent insertion before URSL, pre-operative positive urine culture, and MDR pathogen found preoperatively. In multivariable analysis, only positive urine culture remained significantly associated with the risk of urosepsis after URSL. Conclusions: Patients with positive urine culture before URSL are at significantly higher risk of urosepsis in the postoperative period. Hence, urine culture should be routinely performed before planned endoscopic urolithiasis treatment.

Correlation between Selenium and Zinc Levels and Survival among Prostate Cancer Patients.

The most prevalent type of cancer among males is prostate cancer. Survival is considered quite good, but it can be further improved when risk factors are optimized. One of these factors is micronutrients, including Se and Zn. To our knowledge, the interaction between Se and Zn and prostate cancer remains undescribed. This study aimed to investigate the optimal levels of selenium (Se) and zinc (Zn) and their impact on the survival of individuals diagnosed with prostate cancer. A total of 338 prostate cancer patients were enrolled in this study, which was conducted in Poland between 2009 and 2015. Mass spectrometry, which uses inductively coupled plasma mass, was used to assess serum element levels before treatment. The study participants were categorized into quartiles (QI-QIV) based on the distributions of Se and Zn levels observed among surviving participants. Cox regression was used to assess the association between serum Se and Zn levels and the survival of prostate cancer patients. Our results reveal the effect of combined Se and Zn levels on survival in prostate cancer patients (SeQI-ZnQI vs. SeQIV-ZnQIV; HR = 20.9). These results need further research to establish Se/Zn norms for different populations.

Loss of Upk1a and Upk1b expression is linked to stage progression in urothelial carcinoma of the bladder.

BACKGROUND: Uroplakin-1a (Upk1a) and uroplakin-1b (Upk1b) have recently been identified as diagnostic markers for the distinction of urothelial carcinomas from other solid tumor entities. Both proteins play an important role in the stabilization and strengthening of epithelial cells that line the bladder. METHODS: To evaluate the prognostic role of uroplakin expression in urothelial carcinomas, more than 2700 urothelial neoplasms were analyzed in a tissue microarray format by immunohistochemistry. To further assess the diagnostic role of uroplakin immunohistochemistry, results were compared with preexisting GATA3 data. RESULT: The fraction of Upk1a/Upk1b positive cases decreased slightly from pTaG2 low-grade (88% positive for Upk1a/87% positive for Upk1b) and pTaG2 high-grade (92%/89%) to pTaG3 (83%/88%; p > 0.05) and was lower in muscle-invasive (pT2-4) carcinomas (42%/64%; p < 0.0001/p < 0.0001 for pTa vs. pT2-4). Within pT2-4 carcinomas, high expression of Upk1a and Upk1b was linked to nodal metastasis and lymphatic vessel infiltration (p < 0.05) but unrelated to patient outcome. There were significant associations between Upk1a, Upk1b and GATA3 immunostaining (p < 0.0001 each), but 11% of GATA3 negative cancers were Upk1a/b positive and 8% of Upk1a/b negative cancers were GATA3 positive. Absence of GATA3/Upk1a/b staining was significantly linked to poor patient survival in the subgroup of 126 pT4 carcinomas (p = 0.0004) but not in pT2 and pT3 cancers. CONCLUSIONS: In summary, the results of our study demonstrate that Upk1a and/or Upk1b immunohistochemistry can complement GATA3 for the distinction of urothelial carcinomas. Furthermore, a progressive loss of Upk1a/b expression during stage progression and a prognostic role of the combination GATA3/Upk1a/Upk1b in pT4 carcinomas is evident.

Prognostic Impact and Spatial Interplay of Immune Cells in Urothelial Cancer.

BACKGROUND AND OBJECTIVE: Quantity and the spatial relationship of specific immune cell types can provide prognostic information in bladder cancer. The objective of the study was to characterize the spatial interplay and prognostic role of different immune cell subpopulations in bladder cancer. METHODS: A total of 2463 urothelial bladder carcinomas were immunostained with 21 antibodies using BLEACH&STAIN multiplex fluorescence immunohistochemistry in a tissue microarray format and analyzed using a framework of neuronal networks for an image analysis. Spatial immune parameters were compared with histopathological parameters and overall survival data. KEY FINDINGS AND LIMITATIONS: The identification of > 300 different immune cell subpopulations and the characterization of their spatial relationship resulted in numerous spatial interaction patterns. Thirty-nine immune parameters showed prognostic significance in univariate analyses, of which 16 were independent from pT, pN, and histological grade in muscle-invasive bladder cancer. Among all these parameters, the strongest association with prolonged overall survival was identified for intraepithelial CD8+ cytotoxic T cells (time-dependent area under receiver operating characteristic curve [AUC]: 0.70), while stromal CD8+ T cells were less relevant (AUC: 0.65). A favorable prognosis of inflamed cancers with high levels of "exhaustion markers" suggests that TIM3, PD-L1, PD-1, and CTLA-4 on immune cells do not hinder antitumoral immune response in tumors rich of tumor infiltrating immune cells. CONCLUSIONS AND CLINICAL IMPLICATIONS: The density of intraepithelial CD8+ T cells was the strongest prognostic feature in muscle-invasive bladder cancer. Given that tumor cell killing by CD8+ cytotoxic T lymphocytes through direct cell-to-cell-contacts represents the "terminal end route" of antitumor immunity, the quantity of "tumor cell adjacent CD8+ T cells" may constitute a surrogate for the efficiency of cancer recognition by the immune system that can be measured straightaway in routine pathology as the CD8 labeling index. PATIENT SUMMARY: Quantification of intraepithelial CD8+ T cells, the strongest prognosticfeature identified in muscle-invasive bladder cancer, can easily be assessed by brightfield immunohistochemistry and is therefore "ready to use" for routine pathology.

CEA (CEACAM5) expression is common in muscle-invasive urothelial carcinoma of the bladder but unrelated to the disease course.

Objectives: Carcinoembryonic antigen (CEA) is a cell surface glycoprotein that represents a promising therapeutic target. Serum measurement of shedded CEA can be utilized for monitoring of cancer patients. Material and Methods: To evaluate the potential clinical significance of CEA expression in urothelial bladder neoplasms, CEA was analysed by immunohistochemistry in more than 2500 urothelial bladder carcinomas in a tissue microarray format. Results: CEA staining was largely absent in normal urothelial cells but was observed in 30.4% of urothelial bladder carcinomas including 406 (16.7%) with weak, 140 (5.8%) with moderate, and 192 (7.9%) with strong staining. CEA positivity occurred in 10.9% of 411 pTaG2 low-grade, 32.0% of 178 pTaG2 high-grade, and 43.0% of 93 pTaG3 tumours (p < 0.0001). In 1335 pT2-4 carcinomas, CEA positivity (34.1%) was lower than in pTaG3 tumours. Within pT2-4 carcinomas, CEA staining was unrelated to pT, pN, grade, L-status, V-status, overall survival, recurrence free survival, and cancer specific survival (p > 0.25). Conclusion: CEA increases markedly with grade progression in pTa tumours, and expression occurs in a significant fraction of pT2-4 urothelial bladder carcinomas. The high rate of CEA positivity in pT2-4 carcinomas offers the opportunity of using CEA serum measurement for monitoring the clinical course of these cancers. Moreover, CEA positive urothelial carcinomas are candidates for a treatment by targeted anti-CEA drugs.

Diminishing the Gender-Related Disparity in Survival among Chemotherapy Pre-Treated Patients after Radical Cystectomy-A Multicenter Observational Study.

There is a well-documented problem of inferior outcome of muscle-invasive bladder cancer (MIBC) after radical cystectomy (RC) in women. However, previous studies were conducted before neoadjuvant chemotherapy (NAC) was widely adopted to multidisciplinary management of MIBC. In our study, we assessed the gender-related difference in survival between patients who received NAC and those who underwent upfront RC, in two academic centers. This non-randomized, clinical follow-up study enrolled 1238 consecutive patients, out of whom 253 received NAC. We analyzed survival outcome of RC according to gender between NAC and non-NAC subgroups. We found that female gender was associated with inferior overall survival (OS), compared to males (HR, 1.234; 95%CI 1.046-1.447; p = 0.013) in the overall cohort and in non-NAC patients with ≥pT2 disease (HR, 1.220 95%CI 1.009-1.477; p = 0.041). However, no gender-specific difference was observed in patients exposed to NAC. The 5-year OS in NAC-exposed women in ≤pT1 and ≥pT2 disease, was 69.333% 95%CI (46.401-92.265) and 36.535% (13.134-59.936) respectively, compared to men 77.727% 95%CI (65.952-89.502) and 39.122% 95%CI (29.162-49.082), respectively. The receipt of NAC not only provides downstaging and prolongs patients' survival after radical treatment of MIBC but may also help to diminish the gender specific disparity.

Assessment of the Impact of Pentafecta Parameters Affecting the Quality of Life of Patients Undergoing Laparoscopic Radical Prostatectomy.

Prostate cancer is being detected in increasingly younger men. These patients expect to preserve their current quality of life and quickly recover after treatment. Medical technology and surgical techniques are advancing along with the growing expectations of patients. In addition, the universal method of assessing the quality of outcomes after operations is constantly being researched. As of today, biochemical remission alone, after radical prostatectomy, is insufficient for the patient. Therefore, multi-parametric evaluation methods are being developed, such as trifecta, which assesses biochemical remission, continence, and erectile function. The improvement over the trifecta is the pentafecta, which additionally evaluates postoperative complications and infiltration of surgical margins. Our study was conducted within a group of patients who were surgically treated for prostate cancer in 2017 at the Clinic of Urology and Urological Oncology of the Pomeranian Medical University. We recruited 237 men for the study. From that group, 131 men met the criteria to be included in the analysis. Maintaining continence (87.78%) is the easiest pentafecta parameter to obtain and will have the greatest impact on quality of life in the future. Maintaining biochemical remission (82.44%) is the second most important aspect for the patient. Retaining erectile function is the most difficult pentafecta parameter to obtain (29.01%) while having little impact on the quality of life. Negative surgical margins (66.41%) showed a negligible impact on the quality of life. The occurrence of complications (32.07%) has a negative impact on the quality of life of patients, but only during the treatment of complications.

Did the COVID-19 Pandemic Restrict Access to Emergency Urological Services: Assessment of Reorganisation Effectiveness for Hospital Treatment.

Urolithiasis derived renal colic is a common urological condition. If treated properly, the disease resolves without complications; if not treated, it causes infection and renal failure. The COVID-19 restrictions impacted hospitalised treatment of diseases. We analysed the impact of COVID-19 on renal colic treatment at a hospital in Poland. Clinical and demographic data of patients treated during the COVID-19 era were compared with those treated before this pandemic. During the COVID-19 restrictions, renal colic patient hospital admissions fell significantly. However, more patients presented with chronic renal colic symptoms and urinary tract infections. Nevertheless, the degree of hydronephrosis and the number and location of stones did not differ between the two groups. No marked changes were observed in the chosen treatment options. The observed decrease in emergency admissions of patients with acute renal colic with a simultaneous increase in the rate of infectious stones might indicate that some patients requiring urgent medical help did not report to the emergency department or came later than they would before the pandemic, reporting more serious symptoms. One plausible explanation for this may be that the reorganisation of the healthcare system restricted access to urological care. Moreover, some patients may have delayed their visit to the hospital due to the fear of contracting the SARS-CoV-2 coronavirus.

Tissue immunoexpression of IL-6 and IL-18 in aging men with BPH and MetS and their relationship with lipid parameters and gut microbiota-derived short chain fatty acids.

Recent studies indicate that inflammation is one of the causes of the development of benign prostatic hyperplasia (BPH). Inflammation may result from past infections, metabolic disorders, but also from the state of functioning of the intestinal microbiota. The aim of the study was to assess whether the diagnostic lipid parameters for metabolic syndrome and short-chain fatty acids (SCFAs) are related to the immunoexpression of interleukins in prostate tissue with benign hyperplasia. The study involved 103 men with BPH, who were divided into two groups depending on the presence of MetS. We analysed tissue immunoexpression of two proinflammatory interleukins: IL-6, which is known to be involved in the development of BPH, and IL-18, which has not been analysed so far. The results of our study indicate that men with BPH + MetS in the stroma of the prostate have a significantly higher overall percentage of IL-6+ cells compared to men without MetS (p = 0.034). The analysis of IL-18 immunoexpression in prostate tissue indicated that in men with BPH + MetS, the glandular part of the prostate had a significantly higher percentage of cells with strong IL-18 expression (p = 0.040). We also noticed a relationship between tissue expression of IL-6 and IL-18 and lipid parameters (TG and HDL). We conclude that lipid disorders occurring in men with BPH increase inflammation in the prostate gland. Moreover, it has also been demonstrated for the first time that, indirectly, through SCFAs, the gut microbiota can act to prevent or create an inflammatory microenvironment in the prostate gland.

Combined Modality Bladder-Sparing Therapy for Muscle-Invasive Bladder Cancer: How (Should) We Do It? A Narrative Review.

Organ-sparing combined-modality treatment for muscle-invasive bladder cancer remains underutilized despite high-quality evidence regarding its efficacy, safety, and preservation of quality of life. It may be offered to patients unwilling to undergo radical cystectomy, as well as those unfit for neoadjuvant chemotherapy and surgery. The treatment plan should be tailored to each patient's characteristics, with more intensive protocols offered to patients who are fit for surgery but opt for organ-sparing. After a thorough, debulking transurethral resection of the tumor and neoadjuvant chemotherapy, the response evaluation should trigger further management with either chemoradiation or early cystectomy in non-responders. A hypofractionated, continuous radiotherapy regimen of 55 Gy in 20 fractions with concurrent radiosensitizing chemotherapy with gemcitabine, cisplatin, or 5-fluorouracil and mitomycin C is currently preferred based on clinical trials. The response should be evaluated with repeated transurethral resections of the tumor bed and abdominopelvic-computed tomography after chemoradiation, with quarterly assessments during the first year. Salvage cystectomy should be offered to patients fit for surgery who failed to respond to treatment or developed a muscle-invasive recurrence. Non-muscle-invasive bladder recurrences and upper tract tumors should be treated in line with guidelines for respective primary tumors. Multiparametric magnetic resonance can be used for tumor staging and response monitoring, as it may distinguish disease recurrence from treatment-induced inflammation and fibrosis.

Loss of TROP2 and epithelial cell adhesion molecule expression is linked to grade progression in pTa but unrelated to disease outcome in pT2-4 urothelial bladder carcinomas.

Introduction: Trophoblast cell surface antigen 2 (TROP2; EpCAM2) is a transmembrane glycoprotein which is closely related to EpCAM (EpCAM; EpCAM1). Both proteins share partial overlapping functions in epithelial development and EpCAM expression but have not been comparatively analyzed together in bladder carcinomas. TROP2 constitutes the target for the antibody-drug conjugate Sacituzumab govitecan (SG; TrodelvyTM) which has been approved for treatment of metastatic urothelial carcinoma by the United States Food and Drug administration (FDA) irrespective of its TROP2 expression status. Methods: To evaluate the potential clinical significance of subtle differences in TROP2 and EpCAM expression in urothelial bladder cancer, both proteins were analyzed by multiplex fluorescence immunohistochemistry in combination with a deep-learning based algorithm for automated cell detection on more than 2,700 urothelial bladder carcinomas in a tissue microarray (TMA) format. Results: The staining pattern of TROP2 and EpCAM were highly similar. For both proteins, the staining intensity gradually decreased from pTa G2 low grade (TROP2: 68.8±36.1; EpCAM: 21.5±11.7) to pTa G2 high grade (64.6±38.0; 19.3±12.2) and pTa G3 (52.1±38.7; 16.0±13.0, p<0.001 each). In pT2-4 carcinomas, the average TROP2 and EpCAM staining intensity was intermediate (61.8±40.9; 18.3±12.3). For both proteins, this was significantly lower than in pTa G2 low grade (p<0.001 each) but also higher than in pTa G3 tumors (p=0.022 for TROP2, p=0.071 for EpCAM). Within pT2-4 carcinomas, the TROP2 and EpCAM staining level was unrelated to pT, grade, UICC-category, and overall or tumor-specific patient survival. The ratio TROP2/EpCAM was unrelated to malignant phenotype and patient prognosis. Conclusion: Our data show that TROP2 and EpCAM expression is common and highly interrelated in urothelial neoplasms. Despite of a progressive loss of TROP2/EpCAM during tumor cell dedifferentiation in pTa tumors, the lack of associations with clinicopathological parameters in pT2-4 cancer argues against a major cancer driving role of both proteins for the progression of urothelial neoplasms.

Membrane Transporters and Carriers in Human Seminal Vesicles.

Seminal vesicles play an important role in the male reproductive system, producing seminal fluid and thus adequate environment for sperm. However, mechanisms underlying secretory functions of the seminal vesicles' epithelium have not been defined yet. The aim of the present study was to characterize expression and immunolocalization of selected membrane transporters and carriers in the seminal vesicles. The study included biopsy specimens collected from non-affected parts of seminal vesicles from 53 patients of Caucasian origin subjected for prostatectomy. RT-PCR was used to define expression of 15 genes coding for ABC-family and 37 genes encoding 37 SLC-family transporters/carriers. Immunohistochemistry was used to define localization of 6 transporters. In the seminal vesicles, the following membrane transporters and carriers were defined: ABCA1, ABCB1, ABCB5, ABCB6, ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, ABCC6, ABCG2, SLC01C1, SLC02B1, SLC04A1, SLC04C1, SLC10A1, SLC15A1, SLC15A2, SLC16A1, SLC16A3, SLC19A1, SLC22A1, SLC22A3, SLC22A11, SLC22A18, SLC22A4, SLC22A5, SLC28A1, SLC2A9, SLC33A1, SLC47A1, SLC47A2, SLC51A, SLC51B, SLC7A5, SLC7A6. Age-dependent expression was evidenced for ABCB1, ABCG2, SLC04C1, SLC15A1, SLC16A1, SLC22A11, SLC22A18, SLC47A1 and SLC47A2. ABCG2, P-gp, MRP1, MRP3, MCT1 and LAT1 were localized in the apical membrane and P-gp in the basolateral membrane of the seminal vesicle epithelium. The expression of the membrane transporters and carriers in the seminal vesicle epithelium confirms its secretory and barrier functions.