Vaginal cuff recurrence after radical cystectomy: an under - studied site of bladder cancer relapse

Vaginal cuff recurrence of tumor following radical cystectomy is a rare site of disease recurrence, however it has never been specifically studied. The aim of the study is to evaluate incidence, risk factors, and long-term oncologic outcomes of vaginal cuff recurrence in a cohort of female patients treated with radical cystectomy for invasive urothelial carcinoma of the bladder

Age and Prostate-Specific Antigen Level Prior to Diagnosis Predict Risk of Death from Prostate Cancer.

A single early prostate-specific antigen (PSA) level has been correlated with a higher likelihood of prostate cancer diagnosis and death in younger men. PSA testing in older men has been considered of limited utility. We evaluated prostate cancer death in relation to age and PSA level immediately prior to prostate cancer diagnosis. Using the Veterans Affairs database, we identified 230,081 men aged 50-89 years diagnosed with prostate cancer and at least one prior PSA test between 1999 and 2009. Prostate cancer-specific death over time was calculated for patients stratified by age group (e.g., 50-59 years, through 80-89 years) and PSA range at diagnosis (10 ranges) using Kaplan-Meier methods. Risk of 10-year prostate cancer mortality across age and PSA was compared using log-rank tests with a Bonferroni adjustment for multiple testing. 10.5% of men diagnosed with prostate cancer died of cancer during the 10-year study period (mean follow-up = 3.7 years). Higher PSA values prior to diagnosis predict a higher risk of death in all age groups (p < 0.0001). Within the same PSA range, older age groups are at increased risk for death from prostate cancer (p < 0.0001). For PSA of 7-10 ng/mL, cancer-specific death, 10 years after diagnosis, increased from 7% for age 50-59 years to 51% for age 80-89 years. Men older than 70 years are more likely to die of prostate cancer at any PSA level than younger men, suggesting prostate cancer remains a significant problem among older men (even those aged 80+) and deserves additional study

Surgical strategies for lymphocele prevention in minimally-invasive radical prostatectomy and lymph-node dissection: a systematic review

PURPOSE: Pelvic lymph node dissection (PLND) is an important step during robotic radical prostatectomy (RARP). The collection of lymphatic fluid (lymphocele) is the most common complication with potentially severe impact; therefore different strategies have been proposed to reduce its incidence. MATERIAL AND METHODS: In this systematic review EMBASE, MEDLINE, Cochrane Library and NIH Registry of Clinical Trials were searched for papers including the following interventions: transperitoneal vs extraperitoneal approach, any reconfiguration of the peritoneum, the use of pelvic drains and the use of different sealing techniques and sealing agents. The outcome evaluated was the incidence of symptomatic lymphocele. Both randomized and non-randomized and/or retrospective studies. RESULTS: Twelve studies were included (including one ongoing RCT). Due to the heterogeneity of included studies no meta-analysis was performed. No significant impact was reported by different sealing techniques and agents or by surgical approach. Three retrospective, non-randomized studies showed a potential benefit of peritoneal reconfiguration in order to maximize the peritoneal surface of reabsorption. CONCLUSION: Lymphocele formation is a multi-step and multifactorial event, high quality literature analyzing risk factors and preventive measures is rather scarce. Peritoneal reconfiguration could represent a reasonable option that deserves further evaluation; no other preventive measure is supported by current evidence

Genomic Classifier Augments the Role of Pathological Features in Identifying Optimal Candidates for Adjuvant Radiation Therapy in Patients With Prostate Cancer: Development and Internal Validation of a Multivariable Prognostic Model.

Purpose Despite documented oncologic benefit, use of postoperative adjuvant radiotherapy (aRT) in patients with prostate cancer is still limited in the United States. We aimed to develop and internally validate a risk-stratification tool incorporating the Decipher score, along with routinely available clinicopathologic features, to identify patients who would benefit the most from aRT. Patient and Methods Our cohort included 512 patients with prostate cancer treated with radical prostatectomy at one of four US academic centers between 1990 and 2010. All patients had ≥ pT3a disease, positive surgical margins, and/or pathologic lymph node invasion. Multivariable Cox regression analysis tested the relationship between available predictors (including Decipher score) and clinical recurrence (CR), which were then used to develop a novel risk-stratification tool. Our study adhered to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis guidelines for development of prognostic models. Results Overall, 21.9% of patients received aRT. Median follow-up in censored patients was 8.3 years. The 10-year CR rate was 4.9% vs. 17.4% in patients treated with aRT versus initial observation ( P \u3c .001). Pathologic T3b/T4 stage, Gleason score 8-10, lymph node invasion, and Decipher score \u3e 0.6 were independent predictors of CR (all P \u3c .01). The cumulative number of risk factors was 0, 1, 2, and 3 to 4 in 46.5%, 28.9%, 17.2%, and 7.4% of patients, respectively. aRT was associated with decreased CR rate in patients with two or more risk factors (10-year CR rate 10.1% in aRT v 42.1% in initial observation; P = .012), but not in those with fewer than two risk factors ( P = .18). Conclusion Using the new model to indicate aRT might reduce overtreatment, decrease unnecessary adverse effects, and reduce risk of CR in the subset of patients (approximately 25% of all patients with aggressive pathologic disease in our cohort) who benefit from this therapy

High Serine-arginine Protein Kinase 1 Expression with PTEN Loss Defines Aggressive Phenotype of Prostate Cancer Associated with Lethal Outcome and Decreased Overall Survival

Background: Serine-arginine protein kinase 1 (SRPK1) has been implicated in prostate cancer (PCa) progression. However, its prognostic value and association with ERG and PTEN expression, two of the most common genetic alterations, have not been explored fully. Objective: We assessed the prognostic value of SRPK1 in association with ERG and PTEN in a cohort of patients managed nonsurgically by androgen deprivation therapy (ADT) for advanced disease. Design, setting, and participants: The study cohort consisted of men diagnosed with PCa by transurethral resection of the prostate (TURP; n = 480). The patients were divided into three main groups: incidental (patients with Gleason score [GS] ≤7 with no prior ADT), advanced (patients with GS ≥8 with no prior ADT), and castrate-resistant PCa (patients with prior ADT). Outcome measurements and statistical analysis: A total of 480 TURP samples were assessed by immunohistochemistry for SRPK1, ERG, and PTEN, and results were correlated with Gleason grade group (GG), overall survival (OS), and PCa-specific mortality (PCSM). Results and limitations: High SRPK1 expression was noted in 105/455 (23%) available patient cores. Expression of SRPK1 was associated with Gleason grade grouping (p \u3c 0.0001) with high expression detected in 22/74 (33%) with GG 5. High SRPK1 was not associated with ERG positivity (p = 0.18) but was significantly associated with PTEN intensity (p = 0.001). High SRPK1 was associated with OS (hazard ratio [HR] 1.99; confidence interval [CI]: 1.57–2.54, p \u3c 0.0001) and PCSM (HR 1.64; CI: 1.19–2.26, p \u3c 0.002). Adjusting for Gleason score, patients with high SRPK1 and negative PTEN had the worst clinical outcome for both OS and PCSM compared with other patients (p \u3c 0.0001, HR: 3.02; CI: 1.87–4.88 and HR: 6.40, CI: 3.19–12.85, respectively). Conclusions: High SRPK1 is associated with worse OS and PCSM. Moreover, patients with high SRPK1 expression and loss of PTEN had the worst clinical outcome for OS and cancer-specific mortality. Combined status of SRPK1 and PTEN may provide added value in stratifying patients into various prognostic groups. Patient summary: The expression of serine-arginine protein kinase 1 (SRPK1) combined with PTEN has a significant prognostic role in prostate cancer patients. Patients with high SRPK1 expression and negative PTEN had the worst clinical outcome for overall survival and cancer-specific mortality

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

Impact of the SPOP Mutant Subtype on the Interpretation of Clinical Parameters in Prostate Cancer.

Purpose: Molecular characterization of prostate cancer, including The Cancer Genome Atlas, has revealed distinct subtypes with underlying genomic alterations. One of these core subtypes, SPOP (speckle-type POZ protein) mutant prostate cancer, has previously only been identifiable via DNA sequencing, which has made the impact on prognosis and routinely used risk stratification parameters unclear. Methods: We have developed a novel gene expression signature, classifier (Subclass Predictor Based on Transcriptional Data), and decision tree to predict the SPOP mutant subclass from RNA gene expression data and classify common prostate cancer molecular subtypes. We then validated and further interrogated the association of prostate cancer molecular subtypes with pathologic and clinical outcomes in retrospective and prospective cohorts of 8,158 patients. Results: The subclass predictor based on transcriptional data model showed high sensitivity and specificity in multiple cohorts across both RNA sequencing and microarray gene expression platforms. We predicted approximately 8% to 9% of cases to be SPOP mutant from both retrospective and prospective cohorts. We found that the SPOP mutant subclass was associated with lower frequency of positive margins, extraprostatic extension, and seminal vesicle invasion at prostatectomy; however, SPOP mutant cancers were associated with higher pretreatment serum prostate-specific antigen (PSA). The association between SPOP mutant status and higher PSA level was validated in three independent cohorts. Despite high pretreatment PSA, the SPOP mutant subtype was associated with a favorable prognosis with improved metastasis-free survival, particularly in patients with high-risk preoperative PSA levels. Conclusion: Using a novel gene expression model and a decision tree algorithm to define prostate cancer molecular subclasses, we found that the SPOP mutant subclass is associated with higher preoperative PSA, less adverse pathologic features, and favorable prognosis. These findings suggest a paradigm in which the interpretation of common risk stratification parameters, particularly PSA, may be influenced by the underlying molecular subtype of prostate cancer

TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup.

Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer–associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient\u27s progression to metastatic disease. Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients (n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer–derived murine cell lines. Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches. ©2017 AACR