The prognostic value of perioperative platelet and leukocyte values in patients undergoing radical cystectomy: a prospective long-term cohort study.

INTRODUCTION: Studies assessing the impact of preoperative and first-day postoperative values of leukocytes, thrombocytes, and platelet/leukocyte ratio (PLR) after radical cystectomy (RC) are sparse. We aimed to assess the impact of these factors on long-term survival after RC. METHODS: An analysis of patients undergoing open RC from 2004 to 2023 at our center was performed. Leukocytosis was defined as ≥8,000 leukocytes/µL and thrombocytosis as ≥400,000 thrombocytes/µL. Similarly, the cutoff for PLR was set at 28. A multivariable Cox regression analysis was performed to assess the role of leukocytosis, thrombocytosis and PLR on long-term survival after RC. For all analyses hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs) were estimated. RESULTS: A total of 1,817 patients with a median age of 70 years (IQR: 62-77) were included. Overall, 804 (44%), 175 (10%), and 1,296 (71%) patients presented with leukocytosis, thrombocytosis, and PLR ≥28 preoperatively. Accordingly, 1,414 (78%), 37 (2%), and 249 (14%) patients presented with leukocytosis, thrombocytosis, and PLR ≥28 on the first day after RC. At a median follow-up of 26 months (IQR: 8-68) after RC, 896 (49%) patients died. In the multivariate Cox regression analysis after adjusting for major perioperative risk factors, only preoperative leukocytosis (HR: 1.3, 95%CI: 1.1-1.6, p=0.01), as well as both preoperative and first-day thrombocytosis (HR: 2.1, 95%CI: 1.5-2.9 and HR: 2.8, 95%CI: 1.6-5.1, p<0.001, accordingly) were associated with worse overall survival. CONCLUSION: PLR should not be used as a prognostic marker for survival after RC. On the contrary, preoperative leukocytosis, as well as preoperative and first-day thrombocytosis should raise awareness among clinicians performing RC, since they were independently associated with worse survival after RC.

[68Ga]Ga-FAPI-46 PET/CT for penile cancer - a feasibility study.

PURPOSE: Penile cancer is a rare entity and has a good prognosis in localized stage. Delayed surgical treatment of lymphatic disease is associated with poor overall survival but conventional imaging cannot detect occult lymph node metastasis sufficiently. Imaging cancer related fibroblasts has shown promising results as non-invasive staging tool in various tumor entities but has not yet been evaluated in penile cancer. METHODS: In this single-center pilot study, patients planned for surgical treatment for penile cancer underwent preoperatively [68Ga]Ga-FAPI-46 PET/CT. Post-operative histopathology was compared to [68Ga]Ga-FAPI-46 PET/CT results. RESULTS: From January 2022 to June 2022, a total number 11 patients with histopathologically proven penile cancer underwent surgery and received [68Ga]Ga-FAPI-46 PET/CT prior therapy. 8 primary tumor sites and 4 lymph node regions were analyzed. FAPI uptake was increased on primary tumor site (SUVmax 16.2 (9.1 - 25.8)). Histopathological proven lymph node regions showed highly increased FAPI uptakes (SUVmax 17.9 (16.4 - 23.5) on [68Ga]Ga-FAPI-46 PET/CT. CONCLUSION: In this first pilot cohort, there were no false-positive FAPI uptake which might allow the detection of occult lymph node metastasis by [68Ga]Ga-FAPI-46 PET/CT and might consequently lead to omitting lymph node regions during surgery that had no increased FAPI uptake pre-operatively.

Health-related quality of life following salvage radical prostatectomy for recurrent prostate cancer after radiotherapy or focal therapy.

BACKGROUND: Salvage radical prostatectomy (sRP) is an important treatment option for patients with recurrent prostate cancer (PCa) after radiotherapy (RT) or focal therapy (FT). However, health-related quality of life (HRQOL) after sRP depending on the primary treatment is understudied. METHODS: Patients who underwent Salvage RP for recurrent PCa were analyzed. The primary outcome of this study was HRQOL assessed by the quality-of-life questionnaire (QLQ)-C30 and its prostate specific QLQ-PR25 add-on. Secondary outcomes were functional outcome parameters (erectile function, continence) and biochemical recurrence-free survival (BRFS). Statistical analyses employed the chi-square test, Mann-Whitney U test, and Kaplan-Meier method, with a p value < 0.05 denoting significance. RESULTS: 37 patients with RT as primary treatment (RT-sRP) and 22 patients with focal therapy prior sRP (FT-sRP) were analyzed. Mean global health score was not significantly different preoperatively (71.9 vs. 67.3, p = 0.89) as well as after a median of 32 months follow-up (54.9 vs. 50.6, p = 0.63) with impaired HRQOL after sRP in both groups. Baseline erectile dysfunction was more prevalent in the RT-sRP group (mean IIEF-5: 5.0) than in the FT-sRP group (mean IIEF-5: 8.5, p = 0.037). No differences were observed at follow-up for erectile function (IIEF-5-Score: 0.5 vs 2.5, p = 0.199) and continence (continence rate: 48.4% vs 52.9% (p = 0.763) between the RT-sRP and FT-sRP group. 5-year-BRFS was 60% (RT-sRP) and 68% (FT-sRP, p = 0.849). CONCLUSIONS: sRP impacts HRQOL in patients with PCa after RT and FT with no significant differences. Comparison with HRQOL and BRFS of treatment alternatives is paramount to counsel patients for appropriate treatments.

Impact of preoperative LUTS on Health-Related Quality of Life following Radical Prostatectomy - A propensity score matched longitudinal study.

OBJECTIVES: To assess the impact of preoperative lower urinary tract symptoms (LUTS) on long-term health-related quality of life (HRQOL) up to 10 years after radical prostatectomy (RP) for prostate cancer (PC). METHODS: Within our prospective institutional database of 6487 patients treated with RP for PC (2008- 2020), 2727 patients with preoperative LUTS (IPSS score of ≥8) were identified. A 1:1 propensity-score matched analysis of 3056 men (n=1528 LUTS, n=1528 no LUTS) was conducted. Primary endpoint was HRQOL (based on EORTC QLQ-C30 and PR25). Linear regression models tested the effect of preoperative LUTS on the net change in general HRQOL (p<0.05). RESULTS: Median follow-up was 48 months. Preoperative mean global health status (GHS) score (67.4 vs. 75.7) was significantly lower in the LUTS cohort (p<0.001). Post-RP the difference in general HRQOL between the LUTS cohort and the no-LUTS cohort became smaller (65.7 vs. 67.8), however remaining statistically significant (p=0.037). In long-term follow-up, general HRQOL was comparable between both subcohorts (p-range 0.716 - 0.876). Multivariable linear regression analysis revealed increased preoperative IPSS as an independent predictor for increased perioperative improvement of IPSS (p<0.001) CONCLUSIONS: For patients undergoing RP, preoperative LUTS were associated with a postoperative improvement of HRQOL outcomes. In long-term follow-up HRQOL was comparable to patients without preoperative LUTS. Hence RP is an efficient option to treat PC as well as LUTS in those patients.

The impact of perioperative risk factors on long-term survival after radical cystectomy: a prospective, high-volume cohort study.

INTRODUCTION: Radical cystectomy (RC) is the gold standard for muscle-invasive bladder cancer. Nevertheless, RC is associated with substantial perioperative morbidity and mortality. We aimed to evaluate the role of important perioperative risk factors in predicting long-term survival after RC. METHODS: An analysis of the prospective cohort of patients undergoing open RC from 2004 to 2023 at our center was performed. Patients who died within one month after RC were excluded from the study. A univariate and multivariable Cox regression analysis was performed to assess the role of sex, age, urinary diversion, preoperative values of creatinine and hemoglobin, first-day postoperative values of CRP, leucocytes, and thrombocytes, perioperative Clavien-Dindo complications, perioperative chemotherapy, admission to the intensive or intermediate care unit, as well as type of histology, pathologic T-stage, positive lymph nodes, and positive surgical margins on predicting the long-term overall survival after RC. For all analyses hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs) were estimated. RESULTS: A total of 1,750 patients with a median age of 70 years (IQR: 62-76) were included. Of them, 1,069 (61%) received ileal conduit and 650 (37%) neobladder. Overall, 1,016 (58%) perioperative complications occurred. At a median follow-up of 31 months (IQR: 12-71), 884 (51%) deaths were recorded. In the multivariable Cox regression analysis, increasing age (HR: 1.03, 95%CI: 1.02-1.04, p < 0.001), higher preoperative creatinine values (HR: 1.27, 95%CI: 1.12-1.44, p < 0.001), lower preoperative hemoglobin values (HR: 0.93, 95%CI: 0.89-0.97, p = 0.002), higher postoperative thrombocyte values (HR: 1.01, 95%CI: 1.01-1.02, p = 0.02), Clavien-Dindo 1-2 complications (HR: 1.26, 95%CI: 1.03-1.53, p = 0.02), Clavien-Dindo 3-4 complications (HR: 1.55, 95%CI: 1.22-1.96, p < 0.001), locally advanced bladder cancer (HR: 1.29, 95%CI: 1.06-1.55, p = 0.009), positive lymph nodes (HR: 1.74, 95%CI: 1.45-2.11, p < 0.001), and positive surgical margins (HR: 1.61, 95%CI: 1.29-2.01, p < 0.001) negatively affected long-term survival. CONCLUSION: Beside increased age and worse oncological status, impaired renal function, lower preoperative hemoglobin values, higher postoperative thrombocyte values, and perioperative complications are independent risk factors for mortality in the long term in patients undergoing open RC.

[68 Ga]Ga-FAPI-46 PET/CT for locoregional lymph node staging in urothelial carcinoma of the bladder prior to cystectomy: initial experiences from a pilot analysis.

INTRODUCTION: [68 Ga]Ga-FAPI-46 PET/CT is a novel hybrid imaging method that previously showed additional diagnostic value in the assessment of distant urothelial carcinoma lesions. We hypothesized that patients with bladder cancer benefit from [68 Ga]Ga-FAPI-46 PET/CT prior to radical cystectomy for locoregional lymph node staging. MATERIALS AND METHODS: Eighteen patients underwent [68 Ga]Ga-FAPI-46 PET/CT for evaluation of lymph node (LN) status in predefined LN regions. Two hundred twenty-nine intraoperatively removed LN served as histopathological reference standard. RESULTS: Urothelial carcinoma (UC) spread was found in ten LN in seven different regions (14.3%). Hereby, [68 Ga]Ga-FAPI-46 PET/CT was positive in four out of seven regions (57.1%) and showed significantly increased FAPI uptake compared to non-pathological regions. In the remaining three out of seven (42.9%) regions, [68 Ga]Ga-FAPI-46 PET/CT was rated negative since no pathological increased FAPI uptake was detected or the proximity of the urinary tract prevented a differentiation from physiological uptake. CT was inconspicuous in these three regions. In total, two FAP-positive LN regions were found without histopathological counterpart. Overall, sensitivity, specificity, positive predictive value, and negative predictive value were 57.1%, 95.2%, 66.7%, and 93.0% for PET imaging. CONCLUSION: In summary, this innovative [68 Ga]Ga-FAPI-46 PET/CT method showed high specificity and negative predictive value in patients with bladder UC with a future potential to optimize therapy planning.

Upstaging after Transurethral Resection of the Bladder for Non-Muscle-Invasive Cancer of the Bladder: Who Is at Highest Risk?

INTRODUCTION: Transurethral resection of the bladder (TUR-BT) is the standard initial treatment and diagnosis of bladder cancer (BC). Of note, upstaging into muscle-invasive disease (MIBC) during re-resection occurs in a significant proportion of patients. This study aimed to define risk factors at initial TUR-BT for upstaging. METHODS: TUR-BT between 2009 and 2021 were retrospectively screened (n = 3,237). We included patients with visible tumors that received their primary and re-TUR-BT at our institution. Upstaging was defined as pathological tumor stage progression into MIBC at re-TUR-BT. Clinicopathological variables were analyzed for the impact on upstaging. RESULTS: Two hundred and sixty-six patients/532 TUR-BTs were included in the final analysis. Upstaging occurred in 7.9% (21/266) patients. Patients with upstaging presented with stroma-invasive and papillary non-muscle-invasive BC at primary resection in 85.7% (18/21) and 14.3% (3/21), respectively. Detrusor muscle at primary TUR-BT was significantly less present in patients with upstaging (4.1 vs. 95.9%; p < 0.001). After multivariate analysis, solid tumor configuration (HR: 4.17; 95% CI: 1.23-14.15; p = 0.022) and missing detrusor muscle at initial TUR-BT (HR: 3.58; 95% CI: 1.05-12.24; p = 0.043) were significant risk factors for upstaging into MIBC. CONCLUSIONS: The current study defined two major risk factors for upstaging: missing detrusor muscle and solid tumor configuration. We propose that a second resection should be performed earlier if these risk factors apply.

Oncological impact of perioperative blood transfusion in bladder cancer patients undergoing radical cystectomy: Do we need to consider storage time of blood units, donor age, or gender matching?

BACKGROUND: The oncological impact of perioperative blood transfusions (PBTs) of patients undergoing radical cystectomy (RC) because of bladder cancer (BCa) has been a controversial topic discussed in recent years. The main cause for the contradictory findings of existing studies might be the missing consideration of the storage time of red blood cell units (BUs), donor age, and gender matching. STUDY DESIGN AND METHODS: We retrospectively analyzed BCa patients who underwent RC in our department between 2004 and 2021. We excluded patients receiving BUs before RC, >10 BUs, or RC in a palliative setting. We assessed the effect of blood donor characteristics and storage time on overall survival (OS) and cancer-specific survival (CSS) through univariate and multivariable Cox regression analysis. We also performed a propensity score matching with patients who received BUs and patients who did not on a 1:1 ratio. RESULTS: We screened 1692 patients and included 676 patients for the propensity score matching. In the multivariable analysis, PBT was independently associated with worse OS and CSS (p < .001). Postoperative transfusions were associated with better OS (p = .004) and CSS (p = .008) compared to intraoperative or mixed transfusions. However, there was no influence of blood donor age, storage time, or gender matching on prognosis. DISCUSSION: In our study of BCa patients undergoing RC, we demonstrate that PBT, especially if administered intraoperatively, is an independent risk factor for a worse prognosis. However, storage time, donor age, or gender matching did not negatively affect oncological outcomes. Therefore, the specific selection of blood products does not promise any benefits.

Surgical outcomes of cytoreductive nephrectomy in patients receiving systemic immunotherapy for advanced renal cell carcinoma.

PURPOSE: The use of systemic immune checkpoint blockade before surgery is increasing in patients with metastatic renal cell carcinoma, however, the safety and feasibility of performing consolidative cytoreductive nephrectomy after the administration of systemic therapy are not well described. PATIENTS AND METHODS: A retrospective review of patients undergoing nephrectomy was performed using our prospectively maintained institutional database. Patients who received preoperative systemic immunotherapy were identified, and the risk of postoperative complications were compared to those who underwent surgery without upfront systemic treatment. Perioperative characteristics and surgical complications within 90 days following surgery were recorded. RESULTS: Overall, we identified 220 patients who underwent cytoreductive nephrectomy from April 2015 to December 2022, of which 46 patients (21%) received systemic therapy before undergoing surgery. Unadjusted rates of surgical complications included 20% (n = 35) in patients who did not receive upfront systemic therapy and 20% (n = 9) in those who received upfront systemic immunotherapy. In our propensity score analysis, there was no statistically significant association between receipt of upfront immunotherapy and 90-day surgical complications [odds ratio (OR): 1.82, 95% confidence interval (CI): 0.59-5.14; P = 0.3]. This model, however, demonstrated an association between receipt of upfront immunotherapy and an increased odds of requiring a blood transfusion [OR: 4.53, 95% CI: 1.83-11.7; P = 0.001]. CONCLUSION: In our cohort, there was no significant difference in surgical complications among patients who received systemic therapy before surgery compared to those who did not receive upfront systemic therapy. Cytoreductive nephrectomy is safe and with low rates of complications following the use of systemic therapy.

Patients' Trust in Artificial Intelligence-based Decision-making for Localized Prostate Cancer: Results from a Prospective Trial.

BACKGROUND: Artificial intelligence (AI) has the potential to enhance diagnostic accuracy and improve treatment outcomes. However, AI integration into clinical workflows and patient perspectives remain unclear. OBJECTIVE: To determine patients' trust in AI and their perception of urologists relying on AI, and future diagnostic and therapeutic AI applications for patients. DESIGN, SETTING, AND PARTICIPANTS: A prospective trial was conducted involving patients who received diagnostic or therapeutic interventions for prostate cancer (PC). INTERVENTION: Patients were asked to complete a survey before magnetic resonance imaging, prostate biopsy, or radical prostatectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was patient trust in AI. Secondary outcomes were the choice of AI in treatment settings and traits attributed to AI and urologists. RESULTS AND LIMITATIONS: Data for 466 patients were analyzed. The cumulative affinity for technology was positively correlated with trust in AI (correlation coefficient 0.094; p = 0.04), whereas patient age, level of education, and subjective perception of illness were not (p > 0.05). The mean score (± standard deviation) for trust in capability was higher for physicians than for AI for responding in an individualized way when communicating a diagnosis (4.51 ± 0.76 vs 3.38 ± 1.07; mean difference [MD] 1.130, 95% confidence interval [CI] 1.010-1.250; t924 = 18.52, p < 0.001; Cohen's d = 1.040) and for explaining information in an understandable way (4.57 ± vs 3.18 ± 1.09; MD 1.392, 95% CI 1.275-1.509; t921 = 27.27, p < 0.001; Cohen's d = 1.216). Patients stated that they had higher trust in a diagnosis made by AI controlled by a physician versus AI not controlled by a physician (4.31 ± 0.88 vs 1.75 ± 0.93; MD 2.561, 95% CI 2.444-2.678; t925 = 42.89, p < 0.001; Cohen's d = 2.818). AI-assisted physicians (66.74%) were preferred over physicians alone (29.61%), physicians controlled by AI (2.36%), and AI alone (0.64%) for treatment in the current clinical scenario. CONCLUSIONS: Trust in future diagnostic and therapeutic AI-based treatment relies on optimal integration with urologists as the human-machine interface to leverage human and AI capabilities. PATIENT SUMMARY: Artificial intelligence (AI) will play a role in diagnostic decisions in prostate cancer in the future. At present, patients prefer AI-assisted urologists over urologists alone, AI alone, and AI-controlled urologists. Specific traits of AI and urologists could be used to optimize diagnosis and treatment for patients with prostate cancer.

The Impact of Laser Energy on Functional Outcome Following Holmium Laser Enucleation of the Prostate.

OBJECTIVE: To assess the impact of total laser energy applied, as well as enucleation efficiency on short-term functional outcomes for patients treated for lower urinary tract symptoms (LUTS) with Holmium laser enucleation of the prostate (HoLEP). METHODS: A retrospective analysis of 1593 consecutive patients who underwent HoLEP for LUTS due to benign prostate obstruction in a tertiary care center between January 2018 and January 2021 was performed. Perioperative parameters and short-term functional outcome were evaluated. Spearman's rank correlation and linear regression analysis was applied to identify the relationship between total laser energy applied or enucleation efficiency and functional outcome (P < .05). RESULTS: Median weight of enucleated tissue was 65g, median tissue retrieval percentage was 72.2% and median surgery speed was 0.8g/min. Median laser energy applied was 48.8 kJ, median enucleation efficiency was 1.4g/kJ. No significant correlation between the total laser energy and postoperative International Prostate Symptom Score (IPSS), peak urinary flow (Qmax) or postvoid residual urine volume (PVR) was found (P-range: .473-.969). Likewise, no correlation was found between enucleation efficiency and postoperative IPSS, Qmax, and PVR (P-range: .080-.932). Perioperative improvement of functional outcome (delta IPSS, delta Qmax, and delta PVR) did not correlate with total laser energy applied (P-range: .211-.785) or with enucleation efficiency (P-range: .118-.543). Those results were confirmed in linear regression analysis. CONCLUSION: The results of this study reveal that functional outcome following HoLEP are not dependant on the amount of laser energy applied or enucleation efficiency. Our results should support the increased use of HoLEP as surgical treatment option for LUTS due to BPH.

Absence of detrusor muscle in TUR-BT specimen - can we predict who is at highest risk?

INTRODUCTION: As a high-quality TUR-BT is important to ensure adequate treatment for bladder cancer patients, the aim of the current study is to investigate the impact of patient-related, surgical and tumor-specific parameters on detrusor muscle (DM) absence (primary objective) and to assess the impact of DM on the prognosis after a TUR-BT (secondary objective). PATIENTS AND METHODS: Transurethral resection of bladder tumors (TUR-BTs) between 2009 and 2021 were retrospectively screened (n = 3237). We included 2058 cases (1472 patients) for the primary and 472 patients for secondary objective. Clinicopathological variables including tumor size, localization, multifocality, configuration, operation time and skill-level of the urologist were assessed. We analyzed predictors for missing DM and prognostic factors for recurrence-free survival (RFS) for the complete cohort and subgroups. RESULTS: DM was present in 67.6% (n = 1371/2058). Surgery duration (continuous, minutes) was an independent predictor for absence of DM in the complete cohort (OR:0.98, r:0.012, 95%CI:0.98-0.99, p = 0.001). Other significant risk factors for missing DM were papillary tumors (OR:1.99, r:0.251, 95%CI:1.22-3.27, p = 0.006) in the complete cohort and bladder-roof and posterior-bladder-wall localization for re-resections. Absence of DM in high-grade BC correlated with reduced RFS (HR:1.96, 95%CI:1.0-3.79, p = 0.045). CONCLUSION: Sufficient time for a TUR-BT is mandatory to assure DM in the TUR-BT specimen. Also, cases with more difficult locations of bladder tumors should be performed with utmost surgical diligence and endourological training should incorporate how to perform such operations. Of note, DM correlates with improved oncological prognosis in high-grade BC.

Follicular lymphoma presenting as a seminal vesicle mass: Diagnostic path from prostate MRI to 18F-FDG PET/CT.

A 73-year-old man with biopsy-proven Gleason 3+3 prostate cancer presented with a new mass centered in the seminal vesicles with invasion of the base of the prostate on surveillance prostate MRI. Targeted biopsy showed atypical lymphoid proliferation, suspicious for lymphoma. The patient was referred to the nuclear medicine department for [18F]fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT). Multisite 18F-FDG-avid lymphadenopathy observed, as well as FDG uptake in the new mass. Core biopsy from dominant mesenteric mass revealed follicular lymphoma.

Prognostic Factors for Survival in Patients Undergoing Surveillance After Cytoreductive Nephrectomy.

PURPOSE: The clinical course of patients being placed on surveillance in a cohort of systemic therapy-naïve patients who undergo cytoreductive nephrectomy is not well documented. Thus, we evaluated the clinical course of patients placed on surveillance following cytoreductive nephrectomy and identified predictors of survival. MATERIALS AND METHODS: In this large single-institution study, we retrospectively analyzed metastatic renal cell carcinoma patients who underwent cytoreductive nephrectomy followed by surveillance. Predictors of survival were evaluated using the Kaplan-Meier method with a log-rank test. Patients were risk stratified based on IMDC (International mRCC Database Consortium) and number of metastatic sites (Rini score), with IMDC score ≤1 and ≤2 metastatic organ sites considered favorable risk. Primary end point was systemic therapy-free survival. Secondary end points included intervention-free survival, cancer-specific survival, and overall survival. RESULTS: Median systemic therapy-free survival was 23.6 months (95% CI: 15.1-40.6), intervention-free survival was 11.8 months (95% CI: 8.0-18.4), cancer-specific survival was 54.2 months (95% CI: 46.2-71.4), and overall survival 52.4 months (95% CI: 40.3-66.8). Favorable-risk patients compared to unfavorable-risk patients had longer systemic therapy-free survival (50.6 vs 11.1 months, P < .01), survival (25.2 vs 7.3, P < .01), and cancer-specific survival (71.4 vs 46.2 months, P = .02). CONCLUSIONS: Using risk stratification based on IMDC and number of metastatic sites, surveillance in favorable-risk patients can be utilized for a period without the initiation of systemic therapy. This approach can delay patients' exposure to the side effects of systemic therapy.

P2X1 and P2X7 Receptor Overexpression Is a Negative Predictor of Survival in Muscle-Invasive Bladder Cancer.

Bladder cancer is amongst the most common causes of cancer death worldwide. Muscle-invasive bladder cancer (MIBC) bears a particularly poor prognosis. Overexpression of purinergic P2X receptors (P2XRs) has been associated with worse outcome in several malignant tumors. Here, we investigated the role of P2XRs in bladder cancer cell proliferation in vitro and the prognostic value of P2XR expression in MIBC patients. Cell culture experiments with T24, RT4, and non-transformed TRT-HU-1 cells revealed a link between high ATP concentrations in the cell culture supernatants of bladder cell lines and a higher grade of malignancy. Furthermore, proliferation of highly malignant T24 bladder cancer cells depended on autocrine signaling through P2X receptors. P2X1R, P2X4R, and P2X7R expression was immunohistochemically analyzed in tumor specimens from 173 patients with MIBC. High P2X1R expression was associated with pathological parameters of disease progression and reduced survival time. High combined expression of P2X1R and P2X7R increased the risk of distant metastasis and was an independent negative predictor of overall and tumor-specific survival in multivariate analyses. Our results suggest that P2X1R/P2X7R expression scores are powerful negative prognostic markers in MIBC patients and that P2XR-mediated pathways are potential targets for novel therapeutic strategies in bladder cancer.

Methylation status of various gene loci in localized prostate cancer: Novel biomarkers for diagnostics and biochemical recurrence.

BACKGROUND: Oncologic outcomes for patients with localized prostate cancer (PCa) undergoing radical prostatectomy (RP) can vary widely. Hypermethylation of tumor-associated genes has potential as a novel diagnostic tool and predictive biomarker in PCa. We investigated the methylation status of tumor-associated genes in patients who underwent RP. METHODS: Patients who underwent RP during 2004 to 2008 were matched retrospectively based on post-operative D'Amico risk stratification. Quantitative pyrosequencing was used to analyze methylation status of 10 gene loci in cancerous and adjacent benign tissue from histological specimen. Follow-up was performed according to EAU guideline recommendations. Statistical analyses were performed to correlate methylation levels in cancerous and benign tissue with risk profiles and biochemical recurrence (BCR). RESULTS: The cohort included 71 patients: 22 low-risk, 22 intermediate-risk, and 27 high-risk. Mean follow-up time was 74 months. Methylation status differed significantly between cancerous and adjacent benign tissue for the 5 gene loci GSTP1, APC, RASSF1, TNFRFS10c, and RUNX3 (each P < 0.001). Also, the methylation level was significantly higher in high-risk than in low-risk patients for Endoglin2 and APC (P = 0.026; P = 0.032). Using ROC analysis, hypermethylation of APC in PCa tissue was associated with higher risk of BCR (P = 0.005). CONCLUSION: Methylation status of various gene loci holds diagnostic and predictive potential in PCa. Hypermethylation of APC, RASSF1, TNFRFS10c and RUNX3 were identified as novel PCa-specific biomarkers. Furthermore, increased methylation levels of APC and Endoglin2 were associated with high-risk PCa. Additionally, hypermethylation of APC was associated with increased risk of BCR after RP.

Intratumoral Heterogeneity of Molecular Subtypes in Muscle-invasive Bladder Cancer-An Extensive Multiregional Immunohistochemical Analysis.

BACKGROUND: Molecular bladder cancer (BC) subtypes define distinct biological entities and were shown to predict treatment response in neoadjuvant and adjuvant settings. The extent of intratumoral heterogeneity (ITH) might affect subtyping of individual patients. OBJECTIVE: To comprehensively assess the ITH of molecular subtypes in a cohort of muscle-invasive BC. DESIGN, SETTING, AND PARTICIPANTS: A total of 251 patients undergoing radical cystectomy were screened. Three cores of the tumor center (TC) and three cores of the invasive tumor front (TF) of each patient were assembled in a tissue microarray. Molecular subtypes were determined employing 12 pre-evaluated immunohistochemical markers (FGFR3, CCND1, RB1, CDKN2A, KRT5, KRT14, FOXA1, GATA3, TUBB2B, EPCAM, CDH1, and vimentin). A total of 18 072 spots were evaluated, of which 15 002 spots were assessed based on intensity, distribution, or combination. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Allocation to one of five different molecular subtypes-urothelial like, genomically unstable, small-cell/neuroendocrine like, basal/squamous cell carcinoma like, and mesenchymal like-was conducted for each patient for the complete tumor, individual cores, TF, and TC separately. The primary objective was to assess the ITH between the TF and TC (n = 208 patients). The secondary objective was the evaluation of multiregion ITH (n = 191 patients). An analysis of the composition of ITH cases, association with clinicopathological parameters, and prognosis was conducted. RESULTS AND LIMITATIONS: ITH between the TF and TC was seen in 12.5% (n = 26/208), and ITH defined by at least two different subtypes of any location was seen in 24.6% (n = 47/191). ITH was more frequent in locally confined (pT2) versus advanced (pT ≥3) BC stages (38.7% vs 21.9%, p = 0.046), and pT4 BC presented with significantly more basal subtypes than pT2 BC (26.2% vs 11.5%, p = 0.049). In our cohort, there was no association of subtype ITH with prognosis or accumulation of specific molecular subtypes in ITH cases. The key limitations were missing transcriptomic and mutational genetic validation as well as investigation of ITH beyond subtypes. CONCLUSIONS: Several molecular subtypes can be found in nearly every fourth case of muscle-invasive BC, when using immunohistochemistry. ITH must be given due consideration for subtype-guided strategies in BC. Genomic validation of these results is needed. PATIENT SUMMARY: Different molecular subtypes can be found in many cases of muscle-invasive bladder cancer. This might have implications for individualized, subtype-based therapeutic approaches.

Advances in Imaging-Based Biomarkers in Renal Cell Carcinoma: A Critical Analysis of the Current Literature.

Cross-sectional imaging is the standard diagnostic tool to determine underlying biology in renal masses, which is crucial for subsequent treatment. Currently, standard CT imaging is limited in its ability to differentiate benign from malignant disease. Therefore, various modalities have been investigated to identify imaging-based parameters to improve the noninvasive diagnosis of renal masses and renal cell carcinoma (RCC) subtypes. MRI was reported to predict grading of RCC and to identify RCC subtypes, and has been shown in a small cohort to predict the response to targeted therapy. Dynamic imaging is promising for the staging and diagnosis of RCC. PET/CT radiotracers, such as 18F-fluorodeoxyglucose (FDG), 124I-cG250, radiolabeled prostate-specific membrane antigen (PSMA), and 11C-acetate, have been reported to improve the identification of histology, grading, detection of metastasis, and assessment of response to systemic therapy, and to predict oncological outcomes. Moreover, 99Tc-sestamibi and SPECT scans have shown promising results in distinguishing low-grade RCC from benign lesions. Radiomics has been used to further characterize renal masses based on semantic and textural analyses. In preliminary studies, integrated machine learning algorithms using radiomics proved to be more accurate in distinguishing benign from malignant renal masses compared to radiologists' interpretations. Radiomics and radiogenomics are used to complement risk classification models to predict oncological outcomes. Imaging-based biomarkers hold strong potential in RCC, but require standardization and external validation before integration into clinical routines.