Somatic mutations of MLL4/COMPASS induce cytoplasmic localization providing molecular insight into cancer prognosis and treatment.

Cancer genome sequencing consortiums have recently catalogued an abundance of somatic mutations, across a wide range of human cancers, in the chromatin-modifying enzymes that regulate gene expression. Defining the molecular mechanisms underlying the potentially oncogenic functions of these epigenetic mutations could serve as the basis for precision medicine approaches to cancer therapy. MLL4 encoded by the KMT2D gene highly mutated in a large number of human cancers, is a key histone lysine monomethyltransferase within the Complex of Proteins Associated with Set1 (COMPASS) family that regulates gene expression through enhancer function, potentially functioning as a tumor suppressor. We report that the KMT2D mutations which cause MLL4 protein truncation also alter MLL4's subcellular localization, resulting in loss-of-function in the nucleus and gain-of-function in the cytoplasm. We demonstrate that isogenic correction of KMT2D truncation mutation rescues the aberrant localization phenotype and restores multiple regulatory functions of MLL4, including COMPASS integrity/stabilization, histone H3K4 mono-methylation, enhancer activation, and therefore transcriptional regulation. Moreover, isogenic correction diminishes the sensitivity of KMT2D-mutated cancer cells to targeted metabolic inhibition. Using immunohistochemistry, we identified that cytoplasmic MLL4 is unique to the tissue of bladder cancer patients with KMT2D truncation mutations. Using a preclinical carcinogen model of bladder cancer in mouse, we demonstrate that truncated cytoplasmic MLL4 predicts response to targeted metabolic inhibition therapy for bladder cancer and could be developed as a biomarker for KMT2D-mutated cancers. We also highlight the broader potential for prognosis, patient stratification and treatment decision-making based on KMT2D mutation status in MLL4 truncation-relevant diseases, including human cancers and Kabuki Syndrome.

Surgeon Scorecards Improve Muscle Sampling on Transurethral Resection of Bladder Tumor and Recurrence Outcomes in Patients with Nonmuscle Invasive Bladder Cancer.

PURPOSE: The presence of detrusor muscle is essential for accurate staging of T1 cancers. Detrusor muscle presence can be a quality indicator of transurethral resection of bladder tumor for nonmuscle invasive bladder cancer. We hypothesized that increasing surgeon awareness of personal and institutional detrusor muscle sampling rates could improve resection quality and long-term oncologic outcomes. MATERIALS AND METHODS: A retrospective review of transurethral resections of bladder tumor from 1/2006 to 2/2018 was performed. The presence of detrusor muscle in the pathology report and transurethral resection specimen were extracted from records. Individual surgeon scorecards were created and distributed. Rates of detrusor muscle sampling were compared prior to and 12 months after distribution. Chart review was done to compare 3-year recurrence and progression outcomes before and after distribution of scorecards. RESULTS: The rate of detrusor muscle sampling increased from 36% (1,250/3,488) to 54% (202/373) (p=0.001) in the 12 months after scorecard distribution, ie from 30% (448/1,500) to 55% (91/165) (p <0.001) in Ta tumors and from 47% (183/390) to 72% (42/58) (p <0.001) in T1 tumors. Pathological reporting of muscle also improved for all samples (73%, 2,530/3,488 to 90%, 334/373, p <0.001), Ta (75%, 1,127/1,500 to 94%, 155/165, p <0.001) and T1 (93%, 362/390 to 100%, 58/58, p=0.04). On multivariate Cox regression analysis, the surgeon scorecard was associated with decreased 3-year risk of recurrence (HR 0.63, 95% CI 0.40-0.99). CONCLUSIONS: Creation and distribution of individual surgeon scorecards improved detrusor muscle sampling on transurethral resection and was associated with decreased risk of disease recurrence. Quality evaluation of transurethral resection of bladder tumor may contribute to improved outcomes of patients with nonmuscle invasive bladder cancer.

Diagnosis and Treatment of Early Stage Testicular Cancer: AUA Guideline.

PURPOSE: Testis cancer is the most common solid malignancy in young males. The purpose of this guideline is to provide a useful reference on the effective evidence-based treatment of early stage testicular cancer. METHODS: The systematic review utilized to inform this guideline was conducted by a methodology team at the Johns Hopkins University Evidence-based Practice Center. The methodology team searched using PubMed®, Embase®, and the Cochrane Central Register of Controlled Trials (CENTRAL) from January 1980 through August 2018. The evidence review team also reviewed relevant systematic reviews and references provided by the panel to identify articles that may have been missed by the database searches. RESULTS: When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low). Such evidence-based statements are provided as Strong, Moderate, or Conditional Recommendations. In instances of insufficient evidence, additional guidance is provided as Clinical Principles and Expert Opinions. CONCLUSIONS: This guideline attempts to improve a clinician's ability to evaluate and treat patients with testicular cancer, but higher quality evidence in future trials will be essential to improve level of care for these patients.

Genomic classification and risk stratification of bladder cancer.

Bladder cancer is the fourth most common cancer in men and fifth most common overall. The use of next-generation sequencing (NGS) approaches is crucial to precisely characterize the molecular defects of tumors, and this information could be combined with other clinical data, such as tumor histology and TNM staging, with the goal of precise tumor classification. In many settings, targeted NGS is evaluated in patients with first- and second-line metastatic cancer. Yet, in the decade to come we anticipate increased application of precision oncology at all stages of bladder cancer with the aim of customizing cancer treatment. Here, we review the genomic and transcriptomic features associated with risk stratification in bladder cancer and summarize the current efforts for precision oncology in localized urothelial carcinomas.

Circulating microRNA signature for the diagnosis of very high-risk prostate cancer.

We report the identification of a molecular signature using the Scano-miR profiling platform based on the differential expression of circulating microRNAs (miRNA, miR) in serum samples specific to patients with very high-risk (VHR) prostate cancer (PCa). Five miRNA PCa biomarkers (miR-200c, miR-605, miR-135a*, miR-433, and miR-106a) were identified as useful for differentiating indolent and aggressive forms of PCa. All patients with VHR PCa in the study had elevated serum levels of miR-200c. Circulating miR-433, which was differentially expressed in patients with VHR versus low-risk (LR) forms of PCa, was not detectable by quantitative real-time PCR in samples from healthy volunteers. In blind studies, the five miRNA PCa biomarkers were able to differentiate patients with VHR PCas from those with LR forms as well as healthy individuals with at least 89% accuracy. Biological pathway analysis showed the predictive capability of these miRNA biomarkers for the diagnosis and prognosis of VHR aggressive PCa.

NCCN Guidelines Insights: Bladder Cancer, Version 5.2018.

The NCCN Clinical Practice Guidelines in Oncology for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer. These NCCN Guidelines Insights discuss important updates to the 2018 version of the guidelines, including implications of the 8th edition of the AJCC Cancer Staging Manual on treatment of muscle-invasive bladder cancer and incorporating newly approved immune checkpoint inhibitor therapies into treatment options for patients with locally advanced or metastatic disease.

The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies.

As cells age and are exposed to genotoxic stress, preservation of the genomic code requires multiple DNA repair pathways to remove single-strand or double-strand breaks. Loss of function somatic genomic aberrations or germline deficiency in genes involved in DNA repair can result in acute cell death or, after a latency period, cellular transformation. Therapeutic exploitation of DNA repair by inhibition of poly (adenosine diphosphate [ADP]) ribose polymerases (PARP), a family of enzymes involved in the repair of single-strand and in some cases double-strand breaks, has become a novel cancer treatment. Although the application of PARP inhibitors (PARPis) initially focused on tumors with BRCA1 or BRCA2 deficiencies, synthetic susceptibilities to PARPis have been expanded due to the identification of tumors with mutations pathways involved in DNA damage repair, in particular those that repair double-strand breaks using homologous recombination (HR). There is an increasing appreciation that genitourinary (GU) malignancies, including bladder cancer and especially prostate cancer, contain subsets of patients with germline and somatic alterations in HR genes that may reflect an increased response to PARPis. In this review, the authors describe the mechanisms and rationale of the use of PARPis in patients with GU cancers, summarize previously reported preclinical and clinical trials, and identify ongoing trials to determine how PARPis and strategies targeted at HR repair can have widespread application in patients with GU cancers. Cancer 2017;123:1912-1924. © 2017 American Cancer Society.

Treatment of Non-Metastatic Muscle-Invasive Bladder Cancer: AUA/ASCO/ASTRO/SUO Guideline.

PURPOSE: This multidisciplinary, evidence-based guideline for clinically non-metastatic muscle-invasive bladder cancer focuses on the evaluation, treatment and surveillance of muscle-invasive bladder cancer guided toward curative intent. MATERIALS AND METHODS: A systematic review utilizing research from the Agency for Healthcare Research and Quality as well as additional supplementation by the authors and consultant methodologists was used to develop the guideline. Evidence-based statements were based on body of evidence strengths Grade A, B or C and were designated as Strong, Moderate and Conditional Recommendations with additional statements presented in the form of Clinical Principles or Expert Opinions. RESULTS: For the first time for any type of malignancy, the American Urological Association, American Society of Clinical Oncology, American Society for Radiation Oncology and Society of Urologic Oncology have formulated an evidence-based guideline based on a risk-stratified clinical framework for the management of muscle-invasive urothelial bladder cancer. This document is designed to be used in conjunction with the associated treatment algorithm. CONCLUSIONS: The intensity and scope of care for muscle-invasive bladder cancer should focus on the patient, disease and treatment response characteristics. This guideline attempts to improve a clinician's ability to evaluate and treat each patient, but higher quality evidence in future trials will be essential to improve level of care for these patients.

Bladder Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on systemic therapy for muscle-invasive urothelial bladder cancer, as substantial revisions were made in the 2017 updates, such as new recommendations for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. The complete version of the NCCN Guidelines for Bladder Cancer addresses additional aspects of the management of bladder cancer, including non-muscle-invasive urothelial bladder cancer and nonurothelial histologies, as well as staging, evaluation, and follow-up.

High-Risk of Adverse Pathologic Features in Patients With Clinical T1 High-Grade Bladder Cancer Undergoing Radical Cystectomy.

BACKGROUND: Radical cystectomy (RC) is used to treat select patients with T1 high-grade (T1HG) bladder cancer. However, population-level utilization trends and outcomes for these patients are not well-known. We sought to evaluate treatment patterns and clinicopathologic outcomes of RC for T1HG bladder cancer. PATIENTS AND METHODS: Using the National Cancer Data Base (NCDB) for 1998-2012, we conducted a retrospective cohort study of patients with clinical T1HG bladder cancer. The prevalence of RC used to treat T1HG bladder cancer from 1998-2012 was determined. For years 2010-2012, demographic and cancer-related factors were described and regression analysis was used to examine associations with RC. Oncologic outcomes of RC were described and related to mortality using Cox proportional hazards regression. RESULTS: Treatment of T1HG bladder cancer with RC nearly doubled, from 5.5% during 1998-2000 to 9.9%, during 2010-2012. For 2010-2012, 18,277 patients with T1HG bladder cancer were analyzed. Patients who underwent RC were younger, had fewer comorbidities, and were more often treated at an academic center than those who did not undergo RC. At the time of RC, 41% of patients with T1HG bladder cancer were upstaged (pT2 or greater) and 12.7% had lymph node metastases. The 1- and 3-year survival rates were 0.89 and 0.68, respectively. Extravesical (T3+) disease at RC had the strongest independent hazard (hazard ratio [HR], 2.32; 95% CI, 1.72-3.11) of death other than age of 82 years or older (HR, 3.40; 95% CI, 2.28-5.07). CONCLUSIONS: The use of RC for T1HG bladder cancer has increased in prevalence in recent years but is still not widely used. There are concerning pathologic outcomes in patients with clinical T1HG bladder cancer treated with RC, including high rates of pathologic upstaging and nodal metastases. Future studies are necessary to better risk-stratify patients with T1HG bladder cancer to best select those who will benefit from aggressive therapy with RC.

Prostate Cancer, Version 1.2016.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after an initial diagnosis of prostate cancer and management options for localized, regional, and metastatic disease. Recommendations for disease monitoring, treatment of recurrent disease, and systemic therapy for metastatic castration-recurrent prostate cancer also are included. This article summarizes the NCCN Prostate Cancer Panel's most significant discussions for the 2016 update of the guidelines, which include refinement of risk stratification methods and new options for the treatment of men with high-risk and very-high-risk disease and progressive castration-naïve disease.

NCCN Guidelines Insights: Bladder Cancer, Version 2.2016.

These NCCN Guidelines Insights discuss the major recent updates to the NCCN Guidelines for Bladder Cancer based on the review of the evidence in conjunction with the expert opinion of the panel. Recent updates include (1) refining the recommendation of intravesical bacillus Calmette-Guérin, (2) strengthening the recommendations for perioperative systemic chemotherapy, and (3) incorporating immunotherapy into second-line therapy for locally advanced or metastatic disease. These NCCN Guidelines Insights further discuss factors that affect integration of these recommendations into clinical practice.

Open conversion during minimally invasive radical prostatectomy: impact on perioperative complications and predictors from national data.

PURPOSE: Despite the increased use of minimally invasive radical prostatectomy, open conversion may occur due to surgical complications, surgeon inexperience or failure to progress. We used nationally representative data to quantify the impact of open conversion compared to nonconverted minimally invasive radical prostatectomy and open radical prostatectomy, and identify predictors of open conversion. MATERIALS AND METHODS: Years 2004 to 2010 of the Nationwide Inpatient Sample were queried for patients who underwent radical prostatectomy to analyze the association of open conversion during minimally invasive radical prostatectomy with Clavien complications. Multivariate regression models yielded significant predictors of open conversion. RESULTS: From 2004 to 2010, 134,398 (95% CI 111,509-157,287) minimally invasive radical prostatectomies were performed with a 1.8% (95% CI 1.4-2.1) open conversion rate, translating to 2,360 (95% CI 2,001-2,720) conversions. Open conversion cases had a longer length of stay (4.17 vs 1.71 days, p <0.001) and higher hospital charges ($51,049 vs $37,418, p <0.001) than nonconverted cases. Of open conversion cases 45.2% experienced a complication vs 7.2% and 12.9% of minimally invasive radical prostatectomy and open radical prostatectomy cases, respectively (p <0.001). After adjusting for age and comorbidities, open conversion was associated with significantly increased odds of a Clavien grade 1, 2, 3 and 4 complication compared to nonconverted minimally invasive radical prostatectomy and open radical prostatectomy (OR range 2.913 to 15.670, p <0.001). Significant multivariate predictors of open conversion were obesity (OR 1.916), adhesions (OR 3.060), anemia (OR 5.692) and surgeon volume for minimally invasive radical prostatectomy less than 25 cases per year (OR 7.376) (all p <0.01). CONCLUSIONS: Open conversion during minimally invasive radical prostatectomy is associated with a higher than expected increase in complications compared to open radical prostatectomy and minimally invasive radical prostatectomy after adjusting for age and comorbidities. External validation of predictors of open conversion may prove useful in minimizing open conversion during minimally invasive radical prostatectomy.

The prevalence of persistent prostate cancer after radiotherapy detected at radical cystoprostatectomy for bladder cancer.

PURPOSE: More than half of the men who receive treatment for prostate cancer elect radiotherapy. After radiotherapy recurrence is determined by an increase in prostate specific antigen and not usually by pathological confirmation. We describe the prevalence of persistent gradable prostate cancer in men treated with radiotherapy for prostate cancer at radical cystoprostatectomy for bladder cancer. MATERIALS AND METHODS: A total of 78 patients underwent radiotherapy (brachytherapy and/or external beam radiation) before the development of bladder cancer requiring radical cystectomy at our institution. All tissues were evaluated by a specialized genitourinary pathologist. RESULTS: Median time from radiotherapy to radical cystoprostatectomy was 77 months. Gradable prostate cancer was identified in 45% of patients. Of the tumors 69% were Gleason score 7 or greater, 17% were pT3 or greater and 5% showed positive lymph nodes. Men treated more recently were less likely to have gradable prostate cancer, including 100% before 1980, 49% between 1980 and 2000 and 10% from 2000 to the present (p=0.002) as were those who received external beam radiation alone compared to brachytherapy and combined brachytherapy/external beam radiation (58% vs 27% and 14%, respectively, p=0.005). CONCLUSIONS: After radiotherapy 45% of men had persistent prostate cancer (37% of men with no evidence of disease). A decreased prostate cancer rate was associated with later treatment year and combined brachytherapy/external beam radiation regimens. Similar to men treated with radical cystoprostatectomy for muscle invasive bladder cancer, meticulous attention should be paid during prostate removal in men treated with radiotherapy because many may have persistent prostate cancer. In addition, markers other than prostate specific antigen should be studied in men treated with radiotherapy to better identify those with biochemical recurrence.

Clinical outcome of patients with T1 micropapillary urothelial carcinoma of the bladder.

PURPOSE: We report cancer specific outcomes of micropapillary nonmuscle invasive bladder cancer. MATERIALS AND METHODS: We retrospectively reviewed the records of 36 cases restaged within 3 months of the initial diagnosis of micropapillary nonmuscle invasive bladder cancer. Early radical cystectomy within a 3-month landmark after restaging transurethral bladder tumor resection or conservative treatment with intravesical bacillus Calmette-Guérin, surveillance or deferred radical cystectomy was offered according to surgeon and patient preference. The cumulative incidence of cancer specific mortality and metastasis was estimated using the Kaplan-Meier method. Differences in the cumulative incidence of cancer specific mortality and metastasis between the groups were tested using the log rank test. RESULTS: Median patient age was 68 years (IQR 63-77). The male-to-female ratio was 3:1. At restaging all patients had cT1 disease or less. Early radical cystectomy was performed in 15 patients (42%) while 21 (58%) underwent conservative treatment. Median followup after landmark in cancer specific survivors was 3.1 years (IQR 1.1-5.9). The 5-year cumulative incidence of cancer specific mortality was 17% in the early radical cystectomy group and 25% in the conservative management group for an absolute difference of 7% (95% CI -26-41, p = 0.8). The 5-year cumulative incidence of metastasis was 21% and 34%, respectively, with an absolute difference of 13% (95% CI -23-49, p = 0.9). The extent of the micropapillary component was not significantly associated with cancer specific mortality (p = 0.4) or metastasis (p = 0.9). CONCLUSIONS: Using proper selection criteria, including patient and pathological factors, certain patients in whom cT1 micropapillary urothelial carcinoma was managed conservatively did not have significantly worse outcomes than patients treated with early radical cystectomy.

National trends in the treatment of penile prosthesis infections by explantation alone vs. immediate salvage and reimplantation.

INTRODUCTION: A penile prosthesis infection (PPI) is either treated with explantation of the prosthesis with a possible delayed reimplantation or a salvage procedure with an immediate reimplantation of the prosthesis. AIM: We used a large, all-payer national database to investigate the use of the salvage procedure in the setting of PPI. METHODS: The study used years 2000-2009 of the Nationwide Inpatient Sample to identify PPIs treated with immediate salvage or explantation alone. Admissions were then stratified by various parameters to compare differences in the salvage rates. MAIN OUTCOME MEASURES: Salvage Rate of Penile Prosthesis infection. RESULTS: A total of 1,557 patients were treated with an explantation only (82.7%) or salvage (17.3%) for PPI, a proportion that remained stable over the study period. The patients treated with salvage were younger (60.4 vs. 65.1 years), more likely to be discharged home (87.3% vs. 61.9%), and were less likely to have a severe presentation (7.2% vs. 31.6%) than those who were explanted only (P < 0.001). These factors were confirmed on multivariate regression analysis. The regression also revealed that treatment at rural hospitals had lower odds of salvage than treatment at urban teaching hospitals. Race, comorbid diabetes, and insurance status did not independently affect the salvage rate. There was no significant difference in total hospital charges between groups. CONCLUSIONS: Salvage rates have remained low over the past decade. Our study elucidated several factors decreasing the chances of salvage after PPI including age, severity of presentation, and hospital setting.

Application of the 2013 American Urological Association early detection of prostate cancer guideline: who will we miss?

PURPOSE: The American Urological Association (AUA) published new prostate cancer (CaP) screening guidelines in 2013. We apply the guidelines to a retrospective cohort to compare tumor characteristics of those no longer recommended for screening with those who remain screening candidates. METHODS: We identified cases of screening detected CaP (stage cT1c) in the Surveillance Epidemiology and End Results database from October 2005 to December 2010. The 2013 AUA Guidelines were retrospectively applied to the cohort. Men were categorized into three groups for comparison based on whether or not they would now be recommended for CaP screening (Unscreened, Young Unscreened, and Screened). We compared clinical and pathological characteristics of CaP across study groups. RESULTS: A total of 142,382 men were identified. Screening would no longer be recommended for 40,160. Those no longer recommended for screening had higher median PSA (6.4 vs. 5.8 ng/mL, p < 0.01), more Gleason 7 and ≥8 CaP on prostate biopsy (36.4 vs. 34.8 %, p < 0.001; 12.4 vs. 9.2 %, p < 0.001, respectively) and slightly more Gleason ≥8 CaP (9.0 vs. 7.5 %, p = 0.03), and T3 tumors (17.3 vs. 16.5 %, p = 0.01) at prostatectomy. Nodal and distant metastasis rates were clinically equivalent among men screened and unscreened. Subgroup analysis of young patients (40-54 years old) no longer recommended for screening identified intermediate or high-risk Gleason scores at prostatectomy 57.6 % of the time. CONCLUSIONS: Features of CaP in men no longer recommended for routine screening are largely equivalent to if not worse than those in screened men.