Role of Chromatin Modifying Complexes and Therapeutic Opportunities in Bladder Cancer.

BACKGROUND: Chromatin modifying enzymes, mainly through post translational modifications, regulate chromatin architecture and by extension the underlying transcriptional kinetics in normal and malignant cells. Muscle invasive bladder cancer (MIBC) has a high frequency of alterations in chromatin modifiers, with 76% of tumors exhibiting mutation in at least one chromatin modifying enzyme [1]. Additionally, clonal expansion of cells with inactivating mutations in chromatin modifiers has been identified in the normal urothelium, pointing to a currently unknown role of these proteins in normal bladder homeostasis. OBJECTIVE: To review current knowledge of chromatin modifications and enzymes regulating these processes in Bladder cancer (BCa). METHODS: By reviewing current literature, we summarize our present knowledge of external stimuli that trigger loss of equilibrium in the chromatin accessibility landscape and emerging therapeutic interventions for targeting these processes. RESULTS: Genetic lesions in BCa lead to altered function of chromatin modifying enzymes, resulting in coordinated dysregulation of epigenetic processes with disease progression. CONCLUSION: Mutations in chromatin modifying enzymes are wide-spread in BCa and several promising therapeutic targets for modulating activity of these genes are currently in clinical trials. Further research into understanding how the epigenetic landscape evolves as the disease progresses, could help identify patients who might benefit the most from these targeted therapies.

Survival by T Stage for Patients with Localized Bladder Cancer: Implications for Future Screening Trials.

BACKGROUND: There is insufficient data to recommend screening for bladder cancer (BC). For future BC screening trials, it is important to understand how and if tumor (T) stage can act as a surrogate outcome marker for overall (OS) and cancer-specific (CSS) survival. OBJECTIVE: To characterize OS and CSS between primary tumor (T) stages in non-metastatic bladder cancer (BC) patients. METHODS: Non-metastatic BC patients were identified in the National Cancer Database (NCDB; 2004-2015) (n = 343,163) and National Cancer Institute Surveillance, Epidemiology, and End Results database (SEER) (n = 130,751). Cox multivariable regression compared relationships between T stage (LGTa, HGTa, Tis, LGT1, HGT1, T2-T4) and OS or CSS for all patients and sub-cohorts. RESULTS: Compared to stage LGTa as a reference, overall (SEER; NCDB) and cancer-specific (SEER) survival significantly declined with increasing T stage. Using SEER, OS ranged from HGTa (HR 1.16, CI 1.13-1.21, p < 0.001) to T4 (HR 5.70, CI 5.41-6.00, p < 0.001) with a steep inflection between HGT1 (HR 1.68, CI 1.63-1.73, p < 0.001) and T2 (HR 3.39, CI 3.30-3.49, p < 0.001), which was verified with NCDB. The association of stage and CSS was even more pronounced: HGTa (84% 10 year-CSS, HR 1.94, CI 1.81-2.08, p < 0.001), Tis (82% 10 year-CSS, HR 2.28, CI 2.09-2.47, p < 0.001), LGT1 (84% 10 year-CSS, HR 2.30, CI 2.11-2.51, p < 0.001), HGT1 (72% 10 year-CSS, HR 4.24, CI 4.01-4.47, p < 0.001), T2 (48% 10 year-CSS, HR 12.18, CI 11.57-12.82, p < 0.001), T3 (45% 10 year-CSS, HR 14.60, CI 13.63-15.64, p < 0.001), and T4 (29% 10 year-CSS, HR 22.76, CI 21.19-24.44, p < 0.001). CONCLUSIONS: Earlier T stage at diagnosis was associated with better OS largely due to differences in CSS. A clinically significant difference between Stage I and Stage II was verified herein in multiple cohorts. Therefore, earlier stage at diagnosis, specifically preventing muscle invasive BC, could potentially improve survival.

Delayed Reconstruction of Bulbar Urethral Strictures is Associated with Multiple Interventions, Longer Strictures and More Complex Repairs.

PURPOSE: Prior to urethral reconstruction many patients with stricture undergo a variable period during which endoscopic treatments are performed for recurrent obstructive symptoms. We evaluated the association among urethroplasty delay, endoscopic treatments and subsequent reconstructive outcomes. MATERIALS AND METHODS: We reviewed the records of men who underwent primary bulbar urethroplasty from 2007 to 2014. Those with prior urethroplasty, penile and/or membranous strictures and incomplete data were excluded from analysis. Men were stratified by a urethroplasty delay of less than 5, 5 to 10 or greater than 10 years from diagnosis. RESULTS: A total of 278 primary bulbar urethroplasty cases with complete data were evaluated. Median time between stricture diagnosis and reconstruction was 5 years (IQR 2-10). Patients underwent an average ± SD of 0.9 ± 2.4 endoscopic procedures per year of delay. Relative to less than 5 and 5 to 10 years a delay of greater than 10 years was associated with more endoscopic treatments (median 1 vs 2 vs 5), repeat self-dilations (13% vs 14% vs 34%), strictures longer than 2 cm (40% vs 39% vs 56%) and complex reconstructive techniques (17% vs 17% vs 34%). An increasing number of endoscopic treatments was independently associated with strictures longer than 2 cm (OR 1.06, p = 0.003), which had worse 24-month stricture-free survival than shorter strictures (83% vs 96%, p = 0.0003). Each consecutive direct vision internal urethrotomy was independently associated with the risk of urethroplasty failure (HR 1.19, p = 0.02). CONCLUSIONS: Urethroplasty delay is common and often associated with symptomatic events managed by repeat urethral manipulations. Endoscopic treatments appear to lengthen strictures and increase the complexity of repair.

Urethral Reconstruction in Aging Male Patients.

OBJECTIVE: To report stricture characteristics, complications, and treatment outcomes among elderly men undergoing urethral reconstruction. MATERIALS AND METHODS: A retrospective review of urethroplasty cases and outcomes by a single surgeon from 2007 to 2014 was performed. Men were stratified by decade of life at time of surgery (<50, 50-59, 60-69, ≥70 years). Individuals with a history of hypospadias were excluded. RESULTS: Among 514 urethroplasty procedures, 184 (36%) were evaluated in men ≥60 years. When stratified by decade of life, elderly men were more likely to have a history of radiation therapy (0% vs 5% vs 19% vs 50%; P <.0001) and experience treatment failure (6% vs 16% vs 20% vs 26%; P <.0001) during follow-up (median 63 months). The estimated 60-month stricture recurrence-free survival decreased with increasing age at time of urethroplasty (94% vs 89% vs 78% vs 74%; P <.0001). In patients ≥60 years, success rates of anastomotic, substitution, and urethrostomy techniques were 80%, 65%, and 88%; anastomotic urethroplasty success improved after excluding those patients with prior radiation. After surgery, elderly were more likely to have voiding dysfunction and <90-day Clavien ≥3 complications requiring endoscopic intervention. On multivariable analysis, advancing age per decade beyond 50 years was independently associated with risk of urethroplasty failure-50-59 (hazard ratio [HR] 2.39; P = .02), 60-69 (HR 2.80; P = .009), and ≥70 (HR 3.43; P = .003). CONCLUSION: Urethroplasty is safe and effective in the majority of elderly men. Early reconstructive intervention with anastomotic urethroplasty or urethrostomy techniques may optimize outcomes. Voiding dysfunction and prostatic obstruction are common in this population and should be pursued as clinically indicated.

Characteristics of Idiopathic Urethral Strictures: A Link to Remote Perineal Trauma?

OBJECTIVE: To characterize the physical features and reconstructive outcomes of a series of idiopathic urethral strictures (IUS) in an effort to elucidate the nature of this common yet poorly understood entity. PATIENTS AND METHODS: We retrospectively reviewed our urethroplasty database to identify men undergoing initial urethral reconstruction from 2007 to 2014 at 1 of 3 hospitals (N = 514). Patients were stratified by stricture etiology, including IUS, acute trauma, iatrogenic, hypospadias, balanitis xerotica obliterans, and radiation. IUS that had a known history of subacute or repetitive blunt force to the perineum (horseback riding, avid cycling, motocross, etc.) were subclassified as subacute or repetitive perineal trauma (SRPT). RESULTS: Among 466 men undergoing initial reconstruction with available data, 215 (46%) were IUS cases. The median delay between IUS diagnosis and urethroplasty was 5.2 years, during which time men underwent a median of 2 endoscopic treatments. A total of 51 (24%) IUS cases recalled a distinct history of SRPT. Men with SRPT were slightly younger (median 43 vs 48 years, P = .01) but were remarkably similar in terms of urethral stricture length (2 vs 2 cm, P = .15), location (bulbar 96% vs 89%, P = .41), and treatment success (92% vs 88%; P = .61). Bulbar (-)SRPT and (+)SRPT IUS had similar clinical and morphometric features as those with known acute bulbar trauma with excellent 24-month stricture recurrence-free survival rates (93% vs 92% vs 97%, P = .19). CONCLUSION: IUS have clinical features suggesting that many may be related to unrecognized or repetitive perineal trauma. Although treatment tends to be delayed, IUS have excellent urethroplasty success because most are short bulbar strictures amenable to anastomotic urethroplasty.