Histopathologic, Molecular, and Clinical Profiling of Lymphoepithelioma-like Carcinoma of the Bladder.

Lymphoepithelioma-like carcinoma of the bladder (LELC-B) is a rare histologic subtype characterized by strong immune cell (IC) infiltrates. A better prognosis and favorable response rates to immune checkpoint inhibitors have been described. We aimed to characterize the molecular profiles and IC infiltration of LELC-B for a better understanding of its therapeutic implications. We identified 11 muscle-invasive bladder cancer cases with pure and mixed LELC-B. Programmed cell death ligand-1 (PD-L1) expression and mismatch repair proteins were evaluated using immunohistochemistry. We calculated the tumor mutational burden and characterized mutational profiles using whole-exome DNA sequencing data. Transcriptomic signatures were detected using the NanoString nCounter PanCancer IO360 Panel. Multiplex immunofluorescence of tumor microenvironment (PD-L1, PanCK, α-SMA, vimentin, CD45, and Ki67) and T cells (CD4, CD3, PD-1, CD163, CD8, and FoxP3) was used to quantify cell populations. All LELC-B cases were highly positive for PD-L1 (median tumor proportion score/tumor cell, 70%; range, 20%-100%; median combined positive score, 100; range, 50-100) and mismatch repair proficient and negative for Epstein-Barr virus infection. IC infiltrates were characterized by a high CD8+ T-cell count and high PD-1/PD-L1 expression on immune and tumor cells. LELC-B showed upregulation of signaling pathways involved in IC response. Most common mutations were found in chromatin remodeling genes causing epigenetic dysregulation. All LELC-B cases showed high tumor mutational burden with a median of 39 mutations/Mb (IQR, 29-66 mutations/Mb). In conclusion, LELC-B is a highly immunogenic tumor, showing strong upregulation of PD-1/PD-L1 and making immune checkpoint inhibitors a promising treatment option.

Thulium fiber laser vs. holmium laser enucleation of the prostate: results of a prospective randomized non-inferiority trial.

PURPOSE: Holmium laser enucleation of the prostate (HoLEP) represents the current standard procedure for size-independent surgical therapy of benign prostatic obstruction (BPO). With advent of the novel laser technology thulium fiber laser (TFL), we hypothesized that the functional outcome of TFL enucleation of the prostate (ThuFLEP) is non-inferior compared to HoLEP. METHODS: From October 2021 to October 2022, 150 patients with BPO were recruited for the prospective randomized trial in accordance with CONSORT. Stratified randomization into the arms ThuFLEP (n = 74) or HoLEP (n = 76) was carried out. The primary endpoint was non-inferior international prostate symptom score (IPSS) and quality of life (QoL) at three months after treatment. Secondary endpoints were rates of complications, peak flow, residual urine and operation times. RESULTS: Preoperative characteristics showed no significant differences. Overall IPSS and QoL improved from 21 to 8 and 4 to 1.5, respectively, after three months of follow-up. No statistically significant differences between ThuFLEP and HoLEP were observed regarding median postoperative IPSS (8.5 vs. 7, p > 0.9), QoL (1 vs. 2, p = 0.6), residual urine (48 vs. 30ml, p = 0.065) and peak flow (19 vs. 17ml/s, p > 0.9). Similarly, safety profile was comparable with no statistically significant differences regarding rate of major complications (5.3 vs. 5.4%, p = 0.5), laser hemostasis time (3 vs. 2min, p = 0.2), use of additive electric coagulation (74 vs. 87%, p = 0.06) or electric coagulation time (8 vs. 8min, p = 0.4). CONCLUSIONS: In this prospective, randomized trial ThuFLEP showed non-inferior results compared to HoLEP in terms of functional outcomes measured by IPSS and QoL as primary endpoint. TRIAL REGISTRATION NUMBER: DRKS00032699 (18.09.2023, retrospectively registered).

Tumor-associated macrophages and Tregs influence and represent immune cell infiltration of muscle-invasive bladder cancer and predict prognosis.

INTRODUCTION AND OBJECTIVE: Muscle-invasive urothelial bladder cancer (MIBC) is associated with limited response rates to systemic therapy, risk of recurrence and death. Tumor infiltrating immune cells have been associated with outcome and response to chemo-and immunotherapy in MIBC. We aimed to profile the immune cells in the tumor microenvironment (TME) to predict prognosis in MIBC and responses to adjuvant chemotherapy. METHODS: We performed multiplex immunohistochemistry (IHC) profiling and quantification of immune and stromal cells (CD3, CD4, CD8, CD163, FoxP3, PD-1, and CD45, Vimentin, αSMA, PD-L1, Pan-Cytokeratin, Ki67) in 101 patients with MIBC receiving radical cystectomy. We used uni- and multivariate survival analyses to identify cell types predicting prognosis. Samples were subdivided using K-means clustering for Treg and macrophage infiltration resulting in 3 clusters, Cluster 1: Treg high, cluster 2: macrophage high, cluster 3: Treg and macrophage low. Routine CD68 and CD163 IHC were analyzed with QuPath in an extended cohort of 141 MIBC. RESULTS: High concentrations of macrophages were associated with increased risk of death (HR 10.9, 95% CI 2.8-40.5; p < 0.001) and high concentrations of Tregs were associated with decreased risk of death (HR 0.1, 95% CI 0.01-0.7; p = 0.03) in the multivariate Cox-regression model adjusting for adjuvant chemotherapy, tumor and lymph node stage. Patients in the macrophage rich cluster (2) showed the worst OS with and without adjuvant chemotherapy. The Treg rich cluster (1) showed high levels of effector and proliferating immune cells and had the best survival. Cluster 1 and 2 both were rich in PD-1 and PD-L1 expression on tumor and immune cells. CONCLUSION: Treg and macrophage concentrations in MIBC are independent predictors of prognosis and are important players in the TME. Standard IHC with CD163 for macrophages is feasible to predict prognosis but validation to use immune-cell infiltration, especially to predict response to systemic therapies, is required.

Optimizing identification of consensus molecular subtypes in muscle-invasive bladder cancer: a comparison of two sequencing methods and gene sets using FFPE specimens.

BACKGROUND: Molecular subtypes predict prognosis in muscle-invasive bladder cancer (MIBC) and are explored as predictive markers. To provide a common base for molecular subtyping and facilitate clinical applications, a consensus classification has been developed. However, methods to determine consensus molecular subtypes require validation, particularly when FFPE specimens are used. Here, we aimed to evaluate two gene expression analysis methods on FFPE samples and to compare reduced gene sets to classify tumors into molecular subtypes. METHODS: RNA was isolated from FFPE blocks of 15 MIBC patients. Massive analysis of 3' cDNA ends (MACE) and the HTG transcriptome panel (HTP) were used to retrieve gene expression. We used normalized, log2-transformed data to call consensus and TCGA subtypes with the consensusMIBC package for R using all available genes, a 68-gene panel (ESSEN1), and a 48-gene panel (ESSEN2). RESULTS: Fifteen MACE-samples and 14 HTP-samples were available for molecular subtyping. The 14 samples were classified as Ba/Sq in 7 (50%), LumP in 2 (14.3%), LumU in 1 (7.1%), LumNS in 1 (7.1%), stroma-rich in 2 (14.3%) and NE-like in 1 (7.1%) case based on MACE- or HTP-derived transcriptome data. Consensus subtypes were concordant in 71% (10/14) of cases when comparing MACE with HTP data. Four cases with aberrant subtypes had a stroma-rich molecular subtype with either method. The overlap of the molecular consensus subtypes with the reduced ESSEN1 and ESSEN2 panels were 86% and 100%, respectively, with HTP data and 86% with MACE data. CONCLUSION: Determination of consensus molecular subtypes of MIBC from FFPE samples is feasible using various RNA sequencing methods. Inconsistent classification mainly involves the stroma-rich molecular subtype, which may be the consequence of sample heterogeneity with (stroma)-cell sampling bias and highlights the limitations of bulk RNA-based subclassification. Classification is still reliable when analysis is reduced to selected genes.

Impact of positive surgical margin length and Gleason grade at the margin on oncologic outcomes in patients with nonorgan-confined prostate cancer.

PURPOSE: Positive surgical margins (PSM) represent a poor prognostic factor at radical prostatectomy (RP). To investigate the impact of PSM, its length, the focality and the Gleason grade at the PSM, on the oncologic outcomes in nonorgan-confined RP patients. METHODS: Within a high-volume center database, we identified patients who harbored non-organ-confined (pT3) prostate cancer (PCa) at RP between 2010 and 2016. Only patients without lymph node invasion were included. Kaplan-Meier analyses and multivariable Cox regression models were used to test the effect of PSM on biochemical recurrence (BCR), metastasis, and cancer-specific death after RP in patients without adjuvant radiotherapy. RESULTS: Overall, 3705 patients were identified. Of those, 27.2% (n = 1007) harbored PSM. At 96 months after RP, BCR-free, metastasis-free and cancer-specific survival was 41.6 versus 57.5%, 82.7 versus 88.6%, and 94.7 versus 98.5% for patients with versus without PSM (all p < 0.001). BCR-free, metastasis-free and cancer-specific survival rates at 96 months were 56.7 versus 26.5% (p < 0.001), 94.4 versus 67.4% (p < 0.001), and 100.0 versus 87.1% (p < 0.01) for Gleason pattern 3 versus ≥ 4 at the margin and 45.0 versus 27.8% (p < 0.01), 83.3 versus 82.3% (p = 0.2), and 95.2 versus 92.7% (p = 0.3) for <4 mm versus ≥4 mm length of margin. In multivariable Cox models PSM was an independent predictor for BCR (hazard ratio [HR]:1.53, p < 0.001) and cancer-specific death (HR:2.75, p = 0.02). In subgroups of patients with PSM only, Gleason ≥ 4 at the margin (HR:1.60, p < 0.01) and length of PSM (HR:1.02, p < 0.05) was an independent predictor of BCR. CONCLUSION: PSM represents an independent predictor for worse oncologic outcome in nonorgan-confined PCa at RP. Gleason ≥ 4 at the margin was associated with the development of BCR, metastasis, and with cancer-specific death after RP. Next to margin status, Gleason at the margin and its length carry important information that should be reported for the specimen.

The Impact of Preoperative Double-J Stent on Perioperative Complications, Recurrence, and Quality of Life in Adult Patients Undergoing Pyeloplasty.

PURPOSE: This study aimed to evaluate the impact of preoperative double-J stent (DJ) in pyeloplasty patients on perioperative complications, recurrence, and quality of life (QoL). METHODS: Pyeloplasties due to ureteropelvic junction obstructions between January 2010 and December 2020 were consecutively identified. A standardized follow-up questionnaire was used. Tabulation was made according to preoperative DJ versus no DJ. Subgroup analyses addressed primary robotic pyeloplasties. RESULTS: Of 95 pyeloplasty patients, 62% received a preoperative DJ. Patients with preoperative DJ exhibited higher rates of Clavien-Dindo (CD) 2 (22 vs. 11%) complications, but not of CD3 (8.5 vs. 8.3%, p = 0.5). After a median follow-up of 61 months, 9 patients exhibited a recurrence, of whom 7 had a preoperative DJ. In QoL assessment, comparable findings were made between patients with and without preoperative DJ. In robotic pyeloplasty patients (n = 73), patients with preoperative DJ (58%, n = 42) experienced higher CD3 complication rates, compared to patients without preoperative DJ (12 vs. 6.5%). Moreover, higher rates of recurrences were observed in preoperative DJ patients (12 vs. 3.2%). CONCLUSION: In a contemporary pyeloplasty cohort, the midterm success rate was good with 91%. Our findings suggest that preoperative DJ is associated with higher recurrence rates. However, QoL did not differ between patients with and without preoperative DJ.

External beam radiotherapy and radical prostatectomy are associated with better survival in Asian prostate cancer patients.

OBJECTIVES: To test the effect of race/ethnicity on cancer-specific mortality after radical prostatectomy or external beam radiotherapy in localized prostate cancer patients. METHODS: In the Surveillance, Epidemiology and End Results database 2004-2016, we identified intermediate-risk and high-risk white (n = 151 632), Asian (n = 11 189), Hispanic/Latino (n = 20 077) and African American (n = 32 550) localized prostate cancer patients, treated with external beam radiotherapy or radical prostatectomy. Race/ethnicity-stratified cancer-specific mortality analyses relied on competing risks regression, after propensity score matching for patient and cancer characteristics. RESULTS: Compared with white patients, Asian intermediate- and high-risk external beam radiotherapy patients showed lower cancer-specific mortality (hazard ratio 0.58 and 0.70, respectively, both P ≤ 0.02). Additionally, Asian high-risk radical prostatectomy patients also showed lower cancer-specific mortality than white patients (hazard ratio 0.72, P = 0.04), but not Asian intermediate-risk radical prostatectomy patients (P = 0.08). Conversely, compared with white patients, African American intermediate-risk radical prostatectomy patients showed higher cancer-specific mortality (hazard ratio 1.36, P = 0.01), but not African American high-risk radical prostatectomy or intermediate- and high-risk external beam radiotherapy patients (all P ≥ 0.2). Finally, compared with white people, no cancer-specific mortality differences were recorded for Hispanic/Latino patients after external beam radiotherapy or radical prostatectomy, in both risk levels (P ≥ 0.2). CONCLUSIONS: Relative to white patients, an important cancer-specific mortality advantage applies to intermediate-risk and high-risk Asian prostate cancer patients treated with external beam radiotherapy, and to high-risk Asian patients treated with radical prostatectomy. These observations should be considered in pretreatment risk stratification and decision-making.

Allyl-, Butyl- and Phenylethyl-Isothiocyanate Modulate Akt-mTOR and Cyclin-CDK Signaling in Gemcitabine- and Cisplatin-Resistant Bladder Cancer Cell Lines.

Combined cisplatin-gemcitabine treatment causes rapid resistance development in patients with advanced urothelial carcinoma. The present study investigated the potential of the natural isothiocyanates (ITCs) allyl-isothiocyanate (AITC), butyl-isothiocyanate (BITC), and phenylethyl-isothiocyanate (PEITC) to suppress growth and proliferation of gemcitabine- and cisplatin-resistant bladder cancer cells lines. Sensitive and gemcitabine- and cisplatin-resistant RT112, T24, and TCCSUP cells were treated with the ITCs, and tumor cell growth, proliferation, and clone formation were evaluated. Apoptosis induction and cell cycle progression were investigated as well. The molecular mode of action was investigated by evaluating cell cycle-regulating proteins (cyclin-dependent kinases (CDKs) and cyclins A and B) and the mechanistic target of the rapamycin (mTOR)-AKT signaling pathway. The ITCs significantly inhibited growth, proliferation and clone formation of all tumor cell lines (sensitive and resistant). Cells were arrested in the G2/M phase, independent of the type of resistance. Alterations of both the CDK-cyclin axis and the Akt-mTOR signaling pathway were observed in AITC-treated T24 cells with minor effects on apoptosis induction. In contrast, AITC de-activated Akt-mTOR signaling and induced apoptosis in RT112 cells, with only minor effects on CDK expression. It is concluded that AITC, BITC, and PEITC exert tumor-suppressive properties on cisplatin- and gemcitabine-resistant bladder cancer cells, whereby the molecular action may differ among the cell lines. The integration of these ITCs into the gemcitabine-/cisplatin-based treatment regimen might optimize bladder cancer therapy.

PSA, stage, grade and prostate cancer specific mortality in Asian American patients relative to Caucasians according to the United States Census Bureau race definitions.

BACKGROUND: The United States Census Bureau recommends distinguishing between "Asians" vs. "Native Hawaiians or Other Pacific Islanders" (NHOPI). We tested for prognostic differences according to this stratification in patients with prostate cancer (PCa) of all stages. METHODS: Descriptive statistics, time-trend analyses, Kaplan-Meier plots and multivariate Cox regression models were used to test for differences at diagnosis, as well as for cancer specific mortality (CSM) according to the Census Bureau's definition in either non-metastatic or metastatic patients vs. 1:4 propensity score (PS)-matched Caucasian controls, identified within the Surveillance, Epidemiology and End Results database (2004-2016). RESULTS: Of all 380,705 PCa patients, NHOPI accounted for 1877 (0.5%) vs. 23,343 (6.1%) remaining Asians vs. 93.4% Caucasians. NHOPI invariably harbored worse PCa characteristics at diagnosis. The rates of PSA ≥ 20 ng/ml, Gleason ≥ 8, T3/T4, N1- and M1 stages were highest for NHOPI, followed by Asians, followed by Caucasians (PSA ≥ 20: 18.4 vs. 14.8 vs. 10.2%, Gleason ≥ 8: 24.9 vs. 22.1, vs. 15.9%, T3/T4: 5.5 vs. 4.2 vs. 3.5%, N1: 4.4 vs. 2.8, vs. 2.7%, M1: 8.3 vs. 4.9 vs. 3.9%). Despite the worst PCa characteristics at diagnosis, NHOPI did not exhibit worse CSM than Caucasians. Moreover, despite worse PCa characteristics, Asians exhibited more favorable CSM than Caucasians in comparisons that focussed on non-metastatic and on metastatic patients. CONCLUSIONS: Our observations corroborate the validity of the distinction between NHOPI and Asian patients according to the Census Bureau's recommendation, since these two groups show differences in PSA, grade and stage characteristics at diagnosis in addition to exhibiting differences in CSM even after PS matching and multivariate adjustment.

Holmium laser enucleation of the prostate: efficacy, safety and preoperative management in patients presenting with anticoagulation therapy.

PURPOSE: We evaluated efficacy and safety profile of patients with anticoagulation therapy (AT) undergoing holmium laser enucleation of the prostate (HoLEP). METHODS: Within our prospective institutional database (11/2017 to 11/2019), we analyzed functional outcomes and 30-day complication rates of HoLEP patients according to Clavien-Dindo classification (CLD), stratified according to specific AT vs. no AT. Further analyses consisted of uni- and multivariate logistic regression models (LRM) predicting complications. RESULTS: Of 268 patients undergoing HoLEP, 104 (38.8%) received AT: 25.7% were treated with platelet aggregation inhibitors (PAI), 8.2% with new oral anticoagulants (NOAC) and 4.9% with AT-combinations or coumarins bridged with low molecular weight heparins (LMWH/combination). Patients receiving AT were significantly more comorbid (p < 0.01). Pre- and postoperative maximal flow rates, residual void urine and IPSS at 3 months after surgery were invariably improved after HoLEP for patients with/ without AT. Overall complication rate was 19.5% in patients with no AT vs. 26.1% vs. 27.3 vs. 46.2%, respectively, in patients with PAI, NOAC and LMWH/combination (p < 0.01). Major complications (CLD ≥ 3b) occurred in 6.1% of no AT patients vs. 4.3% vs. 4.5 vs. 0% in patients with PAI, NOAC and LMWH/combination, respectively (p < 0.01). In multivariate LRM, AT was not significantly associated with higher complication rates, whereas high ASA status (OR 2.2, p = 0.04), age (OR 1.04, p = 0.02) and bioptical or incidental prostate cancer (OR 2.5, p = 0.01) represented independent risk factors. CONCLUSION: Despite higher overall complication rates in AT patients, major complications were not more frequent in AT patients. HoLEP is safe and effective in anticoagulated patients.

Catheterization Does Not Improve Course of Disease in Female Patients with Acute Cystitis or Pyelonephritis: Retrospective Analysis of >300 In-Hospital Treated Patients.

PURPOSE: Females with in-hospital treatment for acute cystitis (AC) or pyelonephritis may benefit from catheterization at admission. METHODS: All female patients with AC or pyelonephritis requiring in-hospital treatment at University Hospital Frankfurt (2004-2019) were retrospectively analyzed. Logistic regression models were used to predict the catheter value. RESULTS: Of 310 female patients, 40% harbored AC versus 60% pyelonephritis, of whom 62% and 74% received a catheter at admission: C-reactive protein (CRP) and white blood count (WBC) were significantly elevated in AC and pyelonephritis catheter versus no catheter patients (both p < 0.05). Time to CRP and WBC nadir did not differ between the AC catheter versus no catheter group (both p > 0.05). Conversely, time to CRP nadir was prolonged in pyelonephritis catheter patients. AC and pyelonephritis catheter patients exhibited a prolonged antibiotic treatment and length of stay (LOS, both p < 0.05). In multivariable analyses, CRP >5 ng/mL was a predictor for receiving a catheter in all patients. In AC, a positive urine culture and fever predicted, respectively, prolonged LOS or antibiotic treatment (all p < 0.05). CONCLUSION: Risk factors exist with regard to receiving a catheter and prolonged antibiotic treatment or LOS in females with AC or pyelonephritis. A catheter may not accelerate recovery or WBC nadir.

Life expectancy in metastatic prostate cancer patients according to racial/ethnic groups.

OBJECTIVES: To quantify the magnitude of differences between observed overall survival and respective, age-adjusted Social Security Administration life tables-derived life expectancy in Caucasian, African American, Hispanic/Latino and Asian metastatic prostate cancer patients. Furthermore, to test for differences in cancer-specific mortality and other-cause mortality according to race/ethnicity. METHODS: We relied on the 2004-2006 Surveillance, Epidemiology and End Results database to identify Caucasian, African American, Hispanic/Latino and Asian metastatic prostate cancer patients. Social Security Administration life tables were used to compute 10-year life expectancy for comparisons with observed overall survival. Poisson regression plots showed cancer-specific mortality relative to other-cause mortality for each race/ethnicity. RESULTS: A total of 2574 (64.2%) patients were Caucasian, 753 (18.8%) were African American, 453 (11.3%) were Hispanic/Latino and 227 (5.7%) were Asian, respectively. The median age at diagnosis was 72 years in Caucasian patients, 68 years in African American patients, 70 years in Hispanic/Latino patients and 72 years in Asian patients. Observed overall survival rates were always lower compared with respective predicted life expectancy. The magnitude of the difference between observed overall survival and predicted life expectancy at 10 years was highest in African American patients (-52.2%), followed by Caucasian patients (-48.3%), Hispanic/Latino patients (-46.1%) and Asian patients (-37.4%). African American patients showed the highest cancer-specific mortality rates (71.1%) and second-highest other-cause mortality rates (17.4% vs highest 18.4% in Caucasian patients), despite having the youngest age at diagnosis. Asian patients showed the lowest cancer-specific mortality rates (65.5%, P < 0.0001) and lowest other-cause mortality rates (13.3%, P = 0.04), despite having the oldest age at diagnosis. CONCLUSIONS: Despite having the youngest age at diagnosis, African American patients show the least favorable survival profile in metastatic prostate cancer. Conversely, Asian patients show the most favorable survival profile in metastatic prostate cancer, despite having the oldest age at diagnosis.

Radical prostatectomy improves survival in selected metastatic prostate cancer patients: A North American population-based study.

OBJECTIVE: To test whether radical prostatectomy might result in better survival than external beam radiation therapy in metastatic prostate cancer patients. METHODS: Newly diagnosed metastatic prostate cancer patients with M1a/b substages, treated with radical prostatectomy or external beam radiation therapy were abstracted from the Surveillance, Epidemiology and End Results database (2004-2016). Temporal trend analyses, propensity score matching, cumulative incidence plots, multivariate competing risks regression models and landmark analyses were used. RESULTS: Of 4280 patients, 954 (22.3%) were treated with radical prostatectomy. After propensity score matching, 5-year cancer-specific mortality was 47.0 versus 53.0% in radical prostatectomy versus external beam radiation therapy patients (P = 0.003). In propensity score matched competing risks regression models, radical prostatectomy was associated with lower cancer-specific mortality versus external beam radiation therapy (hazard ratio 0.79, 95% confidence interval 0.79-0.90; P = 0.001). Finally, landmark analyses rejected the bias favoring radical prostatectomy. Finally, in subgroup analyses, we relied on selection criteria that most closely resembled the STAMPEDE criteria and a similar hazard ratio of 0.8 (P < 0.001) was recorded. CONCLUSION: In metastatic prostate cancer, radical prostatectomy results in lower cancer-specific mortality relative to external beam radiation therapy. Even after adjustment for age at diagnosis, prostate-specific antigen and biopsy Gleason grade grouping, lower cancer-specific mortality rates are recorded in radical prostatectomy patients than in external beam radiation therapy patients. As a result, radical prostatectomy should be considered as a treatment option in selected metastatic prostate cancer patients. However, further validation will be provided by ongoing clinical trials.

Sulforaphane Impact on Reactive Oxygen Species (ROS) in Bladder Carcinoma.

Sulforaphane (SFN) is a natural glucosinolate found in cruciferous vegetables that acts as a chemopreventive agent, but its mechanism of action is not clear. Due to antioxidative mechanisms being thought central in preventing cancer progression, SFN could play a role in oxidative processes. Since redox imbalance with increased levels of reactive oxygen species (ROS) is involved in the initiation and progression of bladder cancer, this mechanism might be involved when chemoresistance occurs. This review summarizes current understanding regarding the influence of SFN on ROS and ROS-related pathways and appraises a possible role of SFN in bladder cancer treatment.

Growth, Proliferation and Metastasis of Prostate Cancer Cells Is Blocked by Low-Dose Curcumin in Combination with Light Irradiation.

Although anti-cancer properties of the natural compound curcumin have been reported, low absorption and rapid metabolisation limit clinical use. The present study investigated whether irradiation with visible light may enhance the inhibitory effects of low-dosed curcumin on prostate cancer cell growth, proliferation, and metastasis in vitro. DU145 and PC3 cells were incubated with low-dosed curcumin (0.1-0.4 µg/mL) and subsequently irradiated with 1.65 J/cm2 visible light for 5 min. Controls remained untreated and/or non-irradiated. Cell growth, proliferation, apoptosis, adhesion, and chemotaxis were evaluated, as was cell cycle regulating protein expression (CDK, Cyclins), and integrins of the α- and ß-family. Curcumin or light alone did not cause any significant effects on tumor growth, proliferation, or metastasis. However, curcumin combined with light irradiation significantly suppressed tumor growth, adhesion, and migration. Phosphorylation of CDK1 decreased and expression of the counter-receptors cyclin A and B was diminished. Integrin α and ß subtypes were also reduced, compared to controls. Irradiation distinctly enhances the anti-tumor potential of curcumin in vitro and may hold promise in treating prostate cancer.

Renal Cell Carcinoma: Comparison between Variant Histology and Clear Cell Carcinoma across All Stages and Treatment Modalities.

PURPOSE: We evaluated stage at presentation and cancer specific mortality according to variant histology relative to clear cell renal cell carcinoma. MATERIALS AND METHODS: Within the Surveillance, Epidemiology, and End Results registry (2001-2016) we identified variant histology and clear cell renal cell carcinoma cases. Cumulative incidence plots, multivariate Cox regression models matched for stage, grade and other patient characteristics addressed cancer specific mortality. Subgroup analyses relied on inverse probability treatment weighting according to nephrectomy type. RESULTS: Of all 69,785 patients with renal cell carcinoma 2,495 harbored variant histology (3.6%). Of patients with variant histology 70.1% (1,748) harbored sarcomatoid vs 11.2% (280) collecting duct vs 7.6% (190) mesenchymal vs 3.8% (94) neuroendocrine vs 2.9% (72) renal medullary vs 2.5% (62) mucinous tubular and spindle cell, and 2.0% (49) rhabdoid tumors. All patients with variant histology exhibited more advanced TNM stage at diagnosis than clear cell renal cell carcinoma, except for mucinous tubular and spindle cell. After matching with G4 clear cell renal cell carcinoma, collecting duct (multivariate HR 1.6, p <0.01), sarcomatoid (HR 1.8, p <0.01), renal medullary (HR 1.7, p=0.1) and rhabdoid variant histology (HR 1.5, p=0.1) showed higher cancer specific mortality than clear cell renal cell carcinoma. No cancer specific mortality differences were recorded for mesenchymal, neuroendocrine and mucinous tubular and spindle cell variant histology. In nephrectomy subgroup higher cancer specific mortality was recorded after partial nephrectomy than radical nephrectomy in sarcomatoid variant histology after inverse probability treatment weighting and multivariate adjustment (HR 1.2, p=0.02). CONCLUSIONS: TNM stage at diagnosis is universally more advanced in patients with variant histology, except for mucinous tubular and spindle cell. Cancer specific mortality is higher in collecting duct, sarcomatoid, rhabdoid and renal medullary variant histology, but not in other variant histology. Partial nephrectomy is associated with worse survival in sarcomatoid variant histology but could not be assessed in other variant histology due to small sample size.

Amygdalin Modulates Prostate Cancer Cell Adhesion and Migration In Vitro.

The natural compound, amygdalin, is notably popular with prostate cancer patients as an alternative or complementary treatment option. However, knowledge about its mode of action is sparse. We investigated amygdalin's impact on prostate cancer adhesion and motile behavior. DU-145 and PC3 cancer cells were exposed to amygdalin. Adhesion to human vascular endothelium or immobilized collagen was then explored. The influence of amygdalin on chemotaxis and migration was also investigated, as well as amygdalin induced alteration to surface and total cellular α and ß integrin expression. Integrin knockdown was performed to evaluate the integrin influence on chemotaxis and adhesion. Amygdalin significantly reduced chemotactic activity, migration, and adhesion of DU-145 but not of PC3 cells. Amygdalin elevated integrin α2 in both cell lines. Integrin α6 was reduced by amygdalin only in DU-145 cells, whereas ß1 increased only in PC3 cells. Functional blocking revealed a negative association of α2 with PC3 and DU-145 chemotaxis. The ß1 increase correlated with enhanced chemotaxis, the diminished α6 expression with reduced chemotaxis. Amygdalin acted on prostate cancer cells in vitro. It induced downregulation of α6 integrin in DU-145 but not in PC3 cells, suggesting that exposing certain prostate cancer cells to amygdalin might inhibit metastatic spread promoted by this particular integrin.

Long-term functional outcomes after robotic vs. retropubic radical prostatectomy in routine care: a 6-year follow-up of a large German health services research study.

PURPOSE: To compare long-term functional outcomes after robotic vs. retropubic RP for patients with localized prostate cancer in routine care. METHODS: "HAROW" was a large German noninterventional health services research study that prospectively evaluated the treatment of patients with localized prostate cancer (≤ T2c). We sent validated questionnaires to 1260 patients who underwent RP to evaluate long-term outcomes. RESULTS: After a median follow-up of 6.3 [interquartile range (IQR) 4.8-7.6] years, 42 (3%) patients had died. The return rate of the questionnaire was 76.8% (936/1218). The approach was robotic in 404 and retropubic in 532 patients. In the multivariate analysis, lack of postoperative radiotherapy [odds ratio (OR) 3.1], younger patient age (< 60 years: OR 2.8; 60-69 years: OR 2.1), preoperative urinary continence (OR 2.4), and higher annual hospital caseload (≥ 200 cases: OR 1.6) were independent predictors of urinary continence. The potency rate after nerve-sparing RP in preoperatively potent men was 40.5% (111/274). In the multivariate analysis, younger patient age (< 60 years: OR 17.9; 60-69 years: OR 8.0), lower oncologic risk (OR 2.8), and lack of postoperative radiotherapy (OR 2.2) were independent predictors of potency. CONCLUSION: Younger age and lack of postoperative radiotherapy were associated with better urinary continence and erectile function. Additionally, a high annual caseload (≥ 200 RP/year) was associated with better urinary continence. Younger age, low or intermediated oncological risk and lack of postoperative radiotherapy were independent predictors for a trifecta outcome. The surgical approach did not affect long-term functional outcomes.

Comparison of machine learning algorithms to predict clinically significant prostate cancer of the peripheral zone with multiparametric MRI using clinical assessment categories and radiomic features.

OBJECTIVES: To analyze the performance of radiological assessment categories and quantitative computational analysis of apparent diffusion coefficient (ADC) maps using variant machine learning algorithms to differentiate clinically significant versus insignificant prostate cancer (PCa). METHODS: Retrospectively, 73 patients were included in the study. The patients (mean age, 66.3 ± 7.6 years) were examined with multiparametric MRI (mpMRI) prior to radical prostatectomy (n = 33) or targeted biopsy (n = 40). The index lesion was annotated in MRI ADC and the equivalent histologic slides according to the highest Gleason Grade Group (GrG). Volumes of interest (VOIs) were determined for each lesion and normal-appearing peripheral zone. VOIs were processed by radiomic analysis. For the classification of lesions according to their clinical significance (GrG ≥ 3), principal component (PC) analysis, univariate analysis (UA) with consecutive support vector machines, neural networks, and random forest analysis were performed. RESULTS: PC analysis discriminated between benign and malignant prostate tissue. PC evaluation yielded no stratification of PCa lesions according to their clinical significance, but UA revealed differences in clinical assessment categories and radiomic features. We trained three classification models with fifteen feature subsets. We identified a subset of shape features which improved the diagnostic accuracy of the clinical assessment categories (maximum increase in diagnostic accuracy ΔAUC = + 0.05, p < 0.001) while also identifying combinations of features and models which reduced overall accuracy. CONCLUSIONS: The impact of radiomic features to differentiate PCa lesions according to their clinical significance remains controversial. It depends on feature selection and the employed machine learning algorithms. It can result in improvement or reduction of diagnostic performance. KEY POINTS: • Quantitative imaging features differ between normal and malignant tissue of the peripheral zone in prostate cancer. • Radiomic feature analysis of clinical routine multiparametric MRI has the potential to improve the stratification of clinically significant versus insignificant prostate cancer lesions in the peripheral zone. • Certain combinations of standard multiparametric MRI reporting and assessment categories with feature subsets and machine learning algorithms reduced the diagnostic performance over standard clinical assessment categories alone.

Ethanol-extracted Cameroonian propolis: Antiproliferative effects and potential mechanism of action in prostate cancer.

The present study was conducted to evaluate in vitro and in vivo antiproliferative potential of the Cameroonian propolis and to elucidate its underlying mechanism. In vitro, ethanol-extracted propolis (EEP) was tested on cell growth, cell proliferation, cell cycle, cell death mechanism and cell migration. The cell cycle- and apoptosis-regulating proteins were assessed by Western blotting. In vivo the testosterone-induced benign prostatic hyperplasia (BPH) in Wistar rat was used to evaluate the antiproliferative potential of EEP. EEP reduced DU145 and PC3 cell survival with an IC50 of 70 and 22 µg/ml respectively. It increased the number of late apoptotic cells, the amount of cells in G0/G1 phase in DU145 and PC3 cells at 50 µg/ml. Cell cycle proteins (cdk1, pcdk1 and their related cyclins A and B) were down-regulated in both DU145 and PC3 cells, while cdk2 and pcdk2 were down-regulated only in PC3 cells. The pro-apoptotic Bax protein was up-regulated, while the anti-apoptotic Akt and pAKT, and Bcl-2 proteins were down-regulated. It increased prostate cell adhesion and chemotaxis. EEP reduced prostate weight, volume and epithelial thickness in rats. We demonstrated for the first time that Cameroonian propolis is endowed with in vitro and in vivo antiproliferative properties in the prostate.