Vesicourethral Anastomotic Stenosis Following Radical Prostatectomy: Risk Factors, Natural History, and Treatment Outcomes.

PURPOSE: Vesicourethral anastomotic stenosis after radical prostatectomy is a complication with significant adverse quality-of-life implications. Herein, we identify groups at risk for vesicourethral anastomotic stenosis and further characterize the natural history and treatment patterns. MATERIALS AND METHODS: Years 1987-2013 of a prospectively maintained radical prostatectomy registry were queried for patients with the diagnosis of vesicourethral anastomotic stenosis, defined as symptomatic and inability to pass a 17F cystoscope. Patients with follow-up less than 1 year, preoperative anterior urethral stricture, transurethral resection of prostate, prior pelvic radiotherapy, and metastatic disease were excluded. Logistic regression was performed to identify predictors of vesicourethral anastomotic stenosis. Functional outcomes were characterized. RESULTS: Out of 17,904 men, 851 (4.8%) developed vesicourethral anastomotic stenosis at a median of 3.4 months. Multivariable logistic regression identified associations with vesicourethral anastomotic stenosis including adjuvant radiation, BMI, prostate volume, urine leak, blood transfusion, and nonnerve-sparing techniques. Robotic approach (OR 0.39, P < .01) and complete nerve sparing (OR 0.63, P < .01) were associated with reduced vesicourethral anastomotic stenosis formation. Vesicourethral anastomotic stenosis was independently associated with 1 or more incontinence pads/d at 1 year (OR 1.76, P < .001). Of the patients treated for vesicourethral anastomotic stenosis, 82% underwent endoscopic dilation. The 1- and 5-year vesicourethral anastomotic stenosis retreatment rates were 34% and 42%, respectively. CONCLUSIONS: Patient-related factors, surgical technique, and perioperative morbidity influence the risk of vesicourethral anastomotic stenosis after radical prostatectomy. Ultimately, vesicourethral anastomotic stenosis is independently associated with increased risk of urinary incontinence. Endoscopic management is temporizing for most men, with a high rate of retreatment by 5 years.

External Beam Radiation Therapy With or Without Brachytherapy Boost in Men With Very-High-Risk Prostate Cancer: A Large Multicenter International Consortium Analysis.

PURPOSE: Very-high-risk (VHR) prostate cancer (PC) is an aggressive subgroup with high risk of distant disease progression. Systemic treatment intensification with abiraterone or docetaxel reduces PC-specific mortality (PCSM) and distant metastasis (DM) in men receiving external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT). Whether prostate-directed treatment intensification with the addition of brachytherapy (BT) boost to EBRT with ADT improves outcomes in this group is unclear. METHODS AND MATERIALS: This cohort study from 16 centers across 4 countries included men with VHR PC treated with either dose-escalated EBRT with ≥24 months of ADT or EBRT + BT boost with ≥12 months of ADT. VHR was defined by National Comprehensive Cancer Network (NCCN) criteria (clinical T3b-4, primary Gleason pattern 5, or ≥2 NCCN high-risk features), and results were corroborated in a subgroup of men who met Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trials inclusion criteria (≥2 of the following: clinical T3-4, Gleason 8-10, or PSA ≥40 ng/mL). PCSM and DM between EBRT and EBRT + BT were compared using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression. RESULTS: Among the entire cohort, 270 underwent EBRT and 101 EBRT + BT. After a median follow-up of 7.8 years, 6.7% and 5.9% of men died of PC and 16.3% and 9.9% had DM after EBRT and EBRT + BT, respectively. There was no significant difference in PCSM (sHR, 1.47 [95% CI, 0.57-3.75]; P = .42) or DM (sHR, 0.72, [95% CI, 0.30-1.71]; P = .45) between EBRT + BT and EBRT. Results were similar within the STAMPEDE-defined VHR subgroup (PCSM: sHR, 1.67 [95% CI, 0.48-5.81]; P = .42; DM: sHR, 0.56 [95% CI, 0.15-2.04]; P = .38). CONCLUSIONS: In this VHR PC cohort, no difference in clinically meaningful outcomes was observed between EBRT alone with ≥24 months of ADT compared with EBRT + BT with ≥12 months of ADT. Comparative analyses in men treated with intensified systemic therapy are warranted.

Carboplatin-based adjuvant chemotherapy versus observation after radical cystectomy in patients with pN1-3 urothelial bladder cancer.

PURPOSE: To test the impact of carboplatin-based ACT on overall survival (OS) in patients with pN1-3 cM0 BCa. METHODS: A retrospective analysis was conducted on 1057 patients with pTany pN1-3 cM0 urothelial BCa treated with or without carboplatin-based ACT after radical cystectomy and bilateral lymph-node dissection between 2002 and 2018 at 12 European and North-American hospitals. No patient received neoadjuvant chemotherapy or radiation therapy. Only patients with negative surgical margins at surgery were included. A 3:1 propensity score matching (PSM) was performed using logistic regression to adjust for baseline characteristics. Univariable and multivariable Cox regression analyses were used to predict the effect of carboplatin-based ACT on OS. The Kaplan-Meier method was used to display OS in the matched cohort. RESULTS: Of the 1057 patients included in the study, 69 (6.5%) received carboplatin-based ACT. After PSM, 244 total patients were identified in two cohorts that did not differ for baseline characteristics. Death was recorded in 114 (46.7%) patients over a median follow-up of 19 months. In the multivariable Cox regression analyses, increasing age at surgery (hazard ratio [HR] 1.02, 95% confidence interval [CI] 1.01-1.06, p < 0.001) and increasing number of positive lymph nodes (HR 1.06, 95% CI 1.01-1.07, p = 0.02) were independent predictors of worse OS. The delivery of carboplatin-based ACT was not predictive of improved OS (HR 0.67, 95% CI 0.43-1.04, p = 0.08). The main limitations of this study are its retrospective design and the relatively low number of patients involved. CONCLUSIONS: Carboplatin-based might not improve OS in patients with pN1-3 cM0 BCa. Our results underline the need for alternative therapies for cisplatin-ineligible patients.

Comparison of Multimodal Therapies and Outcomes Among Patients With High-Risk Prostate Cancer With Adverse Clinicopathologic Features.

Importance: The optimal management strategy for high-risk prostate cancer and additional adverse clinicopathologic features remains unknown. Objective: To compare clinical outcomes among patients with high-risk prostate cancer after definitive treatment. Design, Setting, and Participants: This retrospective cohort study included patients with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network [NCCN]) and at least 1 adverse clinicopathologic feature (defined as any primary Gleason pattern 5 on biopsy, clinical T3b-4 disease, ≥50% cores with biopsy results positive for prostate cancer, or NCCN ≥2 high-risk features) treated between 2000 and 2014 at 16 tertiary centers. Data were analyzed in November 2020. Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy boost (BT) with ADT. Guideline-concordant multimodal treatment was defined as RP with appropriate use of multimodal therapy (optimal RP), EBRT with at least 2 years of ADT (optimal EBRT), or EBRT with BT with at least 1 year ADT (optimal EBRT with BT). Main Outcomes and Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis was a secondary outcome. Differences were evaluated using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression models. Results: A total of 6004 men (median [interquartile range] age, 66.4 [60.9-71.8] years) with high-risk prostate cancer were analyzed, including 3175 patients (52.9%) who underwent RP, 1830 patients (30.5%) who underwent EBRT alone, and 999 patients (16.6%) who underwent EBRT with BT. Compared with RP, treatment with EBRT with BT (subdistribution hazard ratio [sHR] 0.78, [95% CI, 0.63-0.97]; P = .03) or with EBRT alone (sHR, 0.70 [95% CI, 0.53-0.92]; P = .01) was associated with significantly improved prostate cancer-specific mortality; there was no difference in prostate cancer-specific mortality between EBRT with BT and EBRT alone (sHR, 0.89 [95% CI, 0.67-1.18]; P = .43). No significant differences in prostate cancer-specific mortality were found across treatment cohorts among 2940 patients who received guideline-concordant multimodality treatment (eg, optimal EBRT alone vs optimal RP: sHR, 0.76 [95% CI, 0.52-1.09]; P = .14). However, treatment with EBRT alone or EBRT with BT was consistently associated with lower rates of distant metastasis compared with treatment with RP (eg, EBRT vs RP: sHR, 0.50 [95% CI, 0.44-0.58]; P < .001). Conclusions and Relevance: These findings suggest that among patients with high-risk prostate cancer and additional unfavorable clinicopathologic features receiving guideline-concordant multimodal therapy, prostate cancer-specific mortality outcomes were equivalent among those treated with RP, EBRT, and EBRT with BT, although distant metastasis outcomes were more favorable among patients treated with EBRT and EBRT with BT. Optimal multimodality treatment is critical for improving outcomes in patients with high-risk prostate cancer.

Development and Validation of a Clinical Prognostic Stage Group System for Nonmetastatic Prostate Cancer Using Disease-Specific Mortality Results From the International Staging Collaboration for Cancer of the Prostate.

Importance: In 2016, the American Joint Committee on Cancer (AJCC) established criteria to evaluate prediction models for staging. No localized prostate cancer models were endorsed by the Precision Medicine Core committee, and 8th edition staging was based on expert consensus. Objective: To develop and validate a pretreatment clinical prognostic stage group system for nonmetastatic prostate cancer. Design, Setting, and Participants: This multinational cohort study included 7 centers from the United States, Canada, and Europe, the Shared Equal Access Regional Cancer Hospital (SEARCH) Veterans Affairs Medical Centers collaborative (5 centers), and the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry (43 centers) (the STAR-CAP cohort). Patients with cT1-4N0-1M0 prostate adenocarcinoma treated from January 1, 1992, to December 31, 2013 (follow-up completed December 31, 2017). The STAR-CAP cohort was randomly divided into training and validation data sets; statisticians were blinded to the validation data until the model was locked. A Surveillance, Epidemiology, and End Results (SEER) cohort was used as a second validation set. Analysis was performed from January 1, 2018, to November 30, 2019. Exposures: Curative intent radical prostatectomy (RP) or radiotherapy with or without androgen deprivation therapy. Main Outcomes and Measures: Prostate cancer-specific mortality (PCSM). Based on a competing-risk regression model, a points-based Score staging system was developed. Model discrimination (C index), calibration, and overall performance were assessed in the validation cohorts. Results: Of 19 684 patients included in the analysis (median age, 64.0 [interquartile range (IQR), 59.0-70.0] years), 12 421 were treated with RP and 7263 with radiotherapy. Median follow-up was 71.8 (IQR, 34.3-124.3) months; 4078 (20.7%) were followed up for at least 10 years. Age, T category, N category, Gleason grade, pretreatment serum prostate-specific antigen level, and the percentage of positive core biopsy results among biopsies performed were included as variables. In the validation set, predicted 10-year PCSM for the 9 Score groups ranged from 0.3% to 40.0%. The 10-year C index (0.796; 95% CI, 0.760-0.828) exceeded that of the AJCC 8th edition (0.757; 95% CI, 0.719-0.792), which was improved across age, race, and treatment modality and within the SEER validation cohort. The Score system performed similarly to individualized random survival forest and interaction models and outperformed National Comprehensive Cancer Network (NCCN) and Cancer of the Prostate Risk Assessment (CAPRA) risk grouping 3- and 4-tier classification systems (10-year C index for NCCN 3-tier, 0.729; for NCCN 4-tier, 0.746; for Score, 0.794) as well as CAPRA (10-year C index for CAPRA, 0.760; for Score, 0.782). Conclusions and Relevance: Using a large, diverse international cohort treated with standard curative treatment options, a proposed AJCC-compliant clinical prognostic stage group system for prostate cancer has been developed. This system may allow consistency of reporting and interpretation of results and clinical trial design.

Low Tristetraprolin Expression Is Associated with Lethal Prostate Cancer.

BACKGROUND: Inflammation is linked to prostate cancer progression and is mediated by NF-κB. Tristetraprolin is a key node of NF-κB activation and we investigated its biological and prognostic role in lethal prostate cancer. METHODS: In vitro assays assessed the function of tristetraprolin and the association between low mRNA tristetraprolin levels and lethal prostate cancer (metastatic disease or death) was assessed across independent prostatectomy cohorts: (i) nested case-control studies from Health Professionals Follow-up Study and Physicians' Health Study, and (ii) prostatectomy samples from Cleveland Clinic, Mayo Clinic, Johns Hopkins and Memorial Sloan Kettering Cancer Center. Tristetraprolin expression levels in prostatectomy samples from patients with localized disease and biopsies of metastatic castration-resistant prostate cancer (mCRPC) were assessed in a Cornell University cohort. RESULTS: In vitro tristetraprolin expression was inversely associated with NF-κB-controlled genes, proliferation, and enzalutamide sensitivity. Men with localized prostate cancer and lower quartile of tumor tristetraprolin expression had a significant, nearly two-fold higher risk of lethal prostate cancer after adjusting for known clinical and histologic prognostic features (age, RP Gleason score, T-stage). Tristetraprolin expression was also significantly lower in mCRPC compared with localized prostate cancer. CONCLUSIONS: Lower levels of tristetraprolin in human prostate cancer prostatectomy tissue are associated with more aggressive prostate cancer and may serve as an actionable prognostic and predictive biomarker. IMPACT: There is a clear need for improved biomarkers to identify patients with localized prostate cancer in need of treatment intensification, such as adjuvant testosterone suppression, or treatment de-intensification, such as active surveillance. Tristetraprolin levels may serve as informative biomarkers in localized prostate cancer.

Development and Validation of a Novel Integrated Clinical-Genomic Risk Group Classification for Localized Prostate Cancer.

Purpose It is clinically challenging to integrate genomic-classifier results that report a numeric risk of recurrence into treatment recommendations for localized prostate cancer, which are founded in the framework of risk groups. We aimed to develop a novel clinical-genomic risk grouping system that can readily be incorporated into treatment guidelines for localized prostate cancer. Materials and Methods Two multicenter cohorts (n = 991) were used for training and validation of the clinical-genomic risk groups, and two additional cohorts (n = 5,937) were used for reclassification analyses. Competing risks analysis was used to estimate the risk of distant metastasis. Time-dependent c-indices were constructed to compare clinicopathologic risk models with the clinical-genomic risk groups. Results With a median follow-up of 8 years for patients in the training cohort, 10-year distant metastasis rates for National Comprehensive Cancer Network (NCCN) low, favorable-intermediate, unfavorable-intermediate, and high-risk were 7.3%, 9.2%, 38.0%, and 39.5%, respectively. In contrast, the three-tier clinical-genomic risk groups had 10-year distant metastasis rates of 3.5%, 29.4%, and 54.6%, for low-, intermediate-, and high-risk, respectively, which were consistent in the validation cohort (0%, 25.9%, and 55.2%, respectively). C-indices for the clinical-genomic risk grouping system (0.84; 95% CI, 0.61 to 0.93) were improved over NCCN (0.73; 95% CI, 0.60 to 0.86) and Cancer of the Prostate Risk Assessment (0.74; 95% CI, 0.65 to 0.84), and 30% of patients using NCCN low/intermediate/high would be reclassified by the new three-tier system and 67% of patients would be reclassified from NCCN six-tier (very-low- to very-high-risk) by the new six-tier system. Conclusion A commercially available genomic classifier in combination with standard clinicopathologic variables can generate a simple-to-use clinical-genomic risk grouping that more accurately identifies patients at low, intermediate, and high risk for metastasis and can be easily incorporated into current guidelines to better risk-stratify patients.

Comparison of Pathological and Oncologic Outcomes of Favorable Risk Gleason Score 3 + 4 and Low Risk Gleason Score 6 Prostate Cancer: Considerations for Active Surveillance.

PURPOSE: Recent NCCN® (National Comprehensive Cancer Network®) Guidelines® show that patients with biopsy Gleason score 3 + 4/Grade Group 2 but otherwise favorable features are active surveillance candidates. However, little is known about the long-term outcomes compared to that in men in the low risk Gleason score 6/Grade Group 1 group. We sought to clarify the risk of adverse features and oncologic outcomes in surgically treated, favorable Grade Group 2 vs 1 cases. MATERIALS AND METHODS: We queried our prospectively maintained radical prostatectomy database for all 8,095 patients with biopsy Grade Group 1 or 2 prostate cancer who otherwise fulfilled the NCCN low risk definition of prostate specific antigen less than 10 ng/ml and cT2a or less, and who underwent radical prostatectomy from 1987 to 2014. Multivariable logistic regression and Kaplan-Meier methods were used to compare pathological and oncologic outcomes. RESULTS: Organ confined disease was present in 93.9% and 82.6% of Grade Group 1 and favorable intermediate risk Grade Group 2 cases while seminal vesicle invasion was noted in 1.7% and 4.7%, and nodal disease was noted in 0.3% and 1.8%, respectively (all p <0.0001). On multivariable logistic regression biopsy proven Grade Group 2 disease was associated with a threefold greater risk of nonorgan confined disease (OR 3.1, 95% CI 1.7-5.7, p <0.001). The incidence of late treatment (more than 90 days from surgery) in Grade Group 1 vs 2 was 3.1% vs 8.5% for hormonal therapy and 6.0% vs 12.2% for radiation (p <0.001). In the Grade Group 1 vs 2 cohorts the 10-year biochemical recurrence-free survival rate was 88.9% vs 81.2% and the 10-year systemic progression-free survival rate was 99% vs 96.5% (each p <0.001). CONCLUSIONS: Men at favorable risk with Grade Group 2 disease who are considering active surveillance should be informed of the risks of harboring adverse pathological features which impact secondary therapies and an increased risk of cancer progression.

Identification of Site-specific Recurrence Following Primary Radiation Therapy for Prostate Cancer Using C-11 Choline Positron Emission Tomography/Computed Tomography: A Nomogram for Predicting Extrapelvic Disease.

BACKGROUND: Management of recurrent prostate cancer (CaP) after radiotherapy (RT) is dependent on accurate localization of the site of recurrent disease. OBJECTIVE: To describe the anatomic patterns and clinical features associated with CaP recurrence following RT identified on advanced imaging. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of 184 patients with a rising prostate-specific antigen (PSA) after RT for CaP. INTERVENTION: C-11 choline positron emission tomography/computed tomography (CholPET). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Recurrence patterns were classified as pelvic soft tissue only (as a surrogate for potentially salvageable disease) versus any extrapelvic disease, and clinical features were compared between patterns. Multivariable logistic regression was used to generate a predictive nomogram for extrapelvic recurrence. Discrimination was assessed with a c-index. RESULTS AND LIMITATIONS: Recurrence site was identified in 161 (87%) patients, with 95 (59%) sites histologically confirmed. Factors associated with the detection of recurrence included the difference between PSA nadir and PSA at CholPET (odds ratio: 1.30, p<0.01) and National Comprehensive Cancer Network high-risk classification (odds ratio: 10.83, p=0.03). One hundred (54.3%) patients recurred in the pelvic soft tissue only, while 61 (33%) had extrapelvic recurrence. Of 21 patients who underwent CholPET prior to meeting the Phoenix criteria of biochemical failure, 15 (71%) had recurrence identified on CholPET with 11 localized to the pelvis. On multivariable analysis, the difference between PSA nadir and PSA at CholPET, time from RT, and National Comprehensive Cancer Network risk group were predictive of recurrence outside of the pelvis, and a nomogram was generated with a c-index of 0.79. CONCLUSIONS: CholPET identified the site of recurrence in 87% of patients with a rising PSA after RT; most commonly within the pelvis in potentially salvageable locations. A predictive nomogram was generated, and pending external validation, this may aid in assessing the risk of disease beyond the pelvis. These findings underscore the importance of advanced imaging when considering management strategies for patients with a rising PSA following primary RT. PATIENT SUMMARY: We identified anatomic patterns of recurrence in patients with a rising prostate-specific antigen after radiotherapy using C-11 choline positron emission tomography/computed tomography. Most recurrences were localized to the pelvis and we were able to generate a tool to aid in disease localization prior to evaluation with advanced imaging.

Adverse Disease Features in Gleason Score 3 + 4 "Favorable Intermediate-Risk" Prostate Cancer: Implications for Active Surveillance.

BACKGROUND: According to a recent National Comprehensive Cancer Network (NCCN) guidelines update, patients with Gleason score (GS) 3 + 4 prostate cancer (PCa) and "favorable intermediate-risk" (FIR) characteristics might be offered active surveillance (AS). However, the risk of unfavorable disease features and its prediction in this subset of patients is not completely understood. OBJECTIVE: To identify the risk of unfavorable disease and potential predictors of adverse outcomes among GS 3 + 4 FIR PCa patients. DESIGN, SETTING, AND PARTICIPANTS: The study included patients with biopsy GS 3 + 4 and otherwise fulfilling the NCCN low-risk definition (prostate-specific antigen [PSA] <10 ng/ml, cT2a or lower) undergoing radical prostatectomy (RP) from 2006 to 2014 at a single institution. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Complete information on PSA, PSA density (PSAD), clinical stage, percentage of positive cores, percentage of maximum surface specimen involvement, and RP pathology were available. GS upgrade and downgrade, non-organ-confined and non-specimen-confined disease, unfavorable disease (pT3-T4 and/or pN1 and/or a pGS ≥4 + 3) were the outcomes. Statistical analysis included descriptive statistics and multivariable logistic regression. RESULTS AND LIMITATIONS: A total of 156 patients (13.1%) experienced GS upgrade; 201 (16.9%) were downgraded. Overall, 205 men (17.2%) harbored non-organ-confined disease, and 295 (24.8%) had unfavorable disease. Age (odds ratio [OR]: 1.06), percentage surface involvement (OR: 1.01), and PSAD (OR: 1.83) were the only significant predictors of upgrade. Age (OR: 1.05), clinical stage (OR: 1.74), percentage of positive cores >50% (OR 1.57), percentage of surface area (OR: 1.02), and perineural invasion (OR: 1.89) were significant predictors of unfavorable disease at RP. The retrospective design is a limitation. CONCLUSIONS: AS is a possible option for a subset of men with FIR GS 3 + 4. However, clinical models alone have a limited role in GS upgrade prediction, and alternative tools warrant further investigation. PATIENT SUMMARY: Patients with Gleason score 3 + 4 at biopsy, low prostate-specific antigen, and low stage might consider the option of active surveillance, but the use of clinical information alone might be not adequate for thorough risk-adapted counseling.

Preclinical evaluation of the supercritical extract of azadirachta indica (neem) leaves in vitro and in vivo on inhibition of prostate cancer tumor growth.

Azadirachta indica, commonly known as neem, has gained worldwide prominence because of its medical properties, namely antitumor, antiviral, anti-inflammatory, antihyperglycemic, antifungal, and antibacterial activities. Despite these promising results, gaps remain in our understanding of the molecular mechanism of action of neem compounds and their potential for use in clinical trials. We investigated supercritical extract of neem leaves (SENL) for the following: molecular targets in vitro, in vivo efficacy to inhibit tumor growth, and bioactive compounds that exert antitumor activity. Treatment of LNCaP-luc2 prostate cancer cells with SENL suppressed dihydrotestosterone-induced androgen receptor and prostate-specific antigen levels. SENL inhibited integrin ß1, calreticulin, and focal adhesion kinase activation in LNCaP-luc2 and PC3 prostate cancer cells. Oral administration of SENL significantly reduced LNCaP-luc2 xenograft tumor growth in mice with the formation of hyalinized fibrous tumor tissue, reduction in the prostate-specific antigen, and increase in AKR1C2 levels. To identify the active anticancer compounds, we fractionated SENL by high-pressure liquid chromatography and evaluated 16 peaks for cytotoxic activity. Four of the 16 peaks exhibited significant cytotoxic activity against prostate cancer cells. Mass spectrometry of the isolated peaks suggested the compounds with cytotoxic activity were nimbandiol, nimbolide, 2',3'-dihydronimbolide, and 28-deoxonimbolide. Analysis of tumor tissue and plasma samples from mice treated with SENL indicated 28-deoxonimbolide and nimbolide as the bioactive compounds. Overall, our data revealed the bioactive compounds in SENL and suggested that the anticancer activity could be mediated through alteration in androgen receptor and calreticulin levels in prostate cancer.

Interaction of adjuvant androgen deprivation therapy with patient comorbidity status on overall survival after radical prostatectomy for high-risk prostate cancer.

BACKGROUND: To evaluate the impact of adjuvant hormonal therapy after radical prostatectomy on overall survival in high-risk prostate cancer patients, stratified by comorbidity status. METHODS: We identified 1247 patients who underwent radical prostatectomy from 1988 to 2004 for high-risk prostate cancer, as defined by National Comprehensive Cancer Network classification. Comorbidity status was stratified by Charlson Comorbidity Index as 0, 1 or >2, as well as by the presence or absence of cardiovascular disease. Overall survival was estimated by the Kaplan-Meier method, and compared within each comorbidity category/adjuvant hormonal therapy strata with the log-rank test. RESULTS: Median patient age was 65 years, and the median postoperative follow up was 11.2 years. In total, 419 patients (34%) received adjuvant hormonal therapy. The distribution of Charlson Comorbidity Index was 0, 1 and ≥ 2 in 861 (69%), 244 (20%) and 142 (11%) patients, respectively. The 10-year overall survival for patients who received adjuvant hormonal therapy versus those who did not was 75% versus 82% (P=0.54) for patients with Charlson Comorbidity Index=0, 72% versus 76% (P=0.83) with Charlson Comorbidity Index=1, and 70% versus 68% (P=0.33) with Charlson Comorbidity Index ≥ 2. Meanwhile, 155 (12%) patients had cardiovascular disease, and the 10-year overall survival for patients with cardiovascular disease who received adjuvant hormonal therapy was 72%, compared with 76% without adjuvant hormonal therapy (P=0.97). On multivariate analysis, receipt of adjuvant hormonal therapy was not associated with non-prostate cancer mortality (P=0.24). CONCLUSIONS: Adjuvant hormonal therapy after radical prostatectomy for high-risk prostate cancer does not increase non-prostate cancer mortality, even among patients with multiple comorbidities. Additional studies are warranted to determine optimal multimodal treatment approach for high-risk patients.

Antiangiogenic Effects and Therapeutic Targets of Azadirachta indica Leaf Extract in Endothelial Cells.

Azadirachta indica (common name: neem) leaves have been found to possess immunomodulatory, anti-inflammatory and anti-carcinogenic properties. The present study evaluates anti-angiogenic potential of ethanol extract of neem leaves (EENL) in human umbilical vein endothelial cells (HUVECs). Treatment of HUVECs with EENL inhibited VEGF induced angiogenic response in vitro and in vivo. The in vitro proliferation, invasion and migration of HUVECs were suppressed with EENL. Nuclear fragmentation and abnormally small mitochondria with dilated cristae were observed in EENL treated HUVECs by transmission electron microscopy. Genome-wide mRNA expression profiling after treatment with EENL revealed differentially regulated genes. Expression changes of the genes were validated by quantitative real-time polymerase chain reaction. Additionally, increase in the expression of HMOX1, ATF3 and EGR1 proteins were determined by immunoblotting. Analysis of the compounds in the EENL by mass spectrometry suggests the presence of nimbolide, 2',3'-dehydrosalannol, 6-desacetyl nimbinene and nimolinone. We further confirmed antiproliferative activity of nimbolide and 2',3'-dehydrosalannol in HUVECs. Our results suggest that EENL by regulating the genes involved in cellular development and cell death functions could control cell proliferation, attenuate the stimulatory effects of VEGF and exert antiangiogenic effects. EENL treatment could have a potential therapeutic role during cancer progression.

Novel molecular targets of Azadirachta indica associated with inhibition of tumor growth in prostate cancer.

Advanced prostate cancer has significant long-term morbidity, and there is a growing interest in alternative and complimentary forms of therapy that will improve the outcomes of patients. Azadirachta indica (common name: neem) contains multiple active compounds that have potent anti-inflammatory and anticancer properties. The present study investigates the novel targets of the anticancer activity of ethanol extract of neem leaves (EENL) in vitro and evaluates the in vivo efficacy in the prostate cancer models. Analysis of the components in the EENL by mass spectrometry suggests the presence of 2',3'-dehydrosalannol, 6-desacetyl nimbinene, and nimolinone. Treatment of C4-2B and PC-3M-luc2 prostate cancer cells with EENL inhibited the cell proliferation. Genome-wide expression profiling, using oligonucleotide microarrays, revealed genes differentially expressed with EENL treatment in prostate cancer cells. Functional analysis unveiled that most of the up-regulated genes were associated with cell death, and drug metabolism, and the down-regulated genes were associated with cell cycle, DNA replication, recombination, and repair functions. Quantitative PCR confirmed significant up-regulation of 40 genes and immunoblotting revealed increase in the protein expression levels of HMOX1, AKR1C2, AKR1C3, and AKR1B10. EENL treatment inhibited the growth of C4-2B and PC-3M-luc2 prostate cancer xenografts in nude mice. The suppression of tumor growth is associated with the formation of hyalinized fibrous tumor tissue and the induction of cell death by apoptosis. These results suggest that EENL-containing natural bioactive compounds could have potent anticancer property and the regulation of multiple cellular pathways could exert pleiotrophic effects in prevention and treatment of prostate cancer.