Publications by authors named "Vikram Narayan"

65 Publications

Digest: Positive selection and recombination shape the genomic landscape in flycatchers.

Evolution 2021 Jul 14. Epub 2021 Jul 14.

School of Biological Sciences, The University of Queensland, St. Lucia, QLD, 4072, Australia.

Whether background selection is sufficient to explain observed genomic differentiation is a long-standing debate. Using four species of flycatcher, Chase et al. addressed this issue and found that the effect of background selection may not be as great as previously thought. Instead, both positive selection and recombination were shown to have a significant effect on genomic differentiation.
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http://dx.doi.org/10.1111/evo.14309DOI Listing
July 2021

Digest: Does size matter? Condition-dependent sexual selection in Drosophila melanogaster.

Evolution 2021 Jun 28. Epub 2021 Jun 28.

Institute of Evolutionary Biology, University of Edinburgh, Ashworth Laboratories, Edinburgh, UK.

What conditions favor competitive outcomes at different stages of the reproductive process? De Nardo et al. found that in Drosophila melanogaster, the evolution of male secondary sexual traits was influenced by sexual selection through mating success and competitive fertilization.
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http://dx.doi.org/10.1111/evo.14294DOI Listing
June 2021

Gene Expression Profiling of Muscle-Invasive Bladder Cancer With Secondary Variant Histology.

Am J Clin Pathol 2021 Jun 22. Epub 2021 Jun 22.

Department of Urology, Erasmus MC, Cancer Institute Rotterdam,  The Netherlands.

Objectives: To determine the potential impact of the presence of secondary variant histology on the gene expression profiles of muscle-invasive bladder cancer (MIBC) tumors.

Methods: For six tumors, revised samples were collected from urothelial and secondary variant components (cohort A). The commercial cohort (cohort B) consisted of the anonymized gene expression profiles of 173 patients with MIBC. Samples were obtained from the clinical use of the Decipher Bladder test that were available as part of the Decipher GRID prospective registry (NCT02609269). Secondary variant presence in cohort B was abstracted from institutional pathology reports. For the commercial cohort, only the urothelial carcinoma component was profiled.

Results: Molecular subtyping of both urothelial and variant components found micropapillary and nested cases were classified as a luminal subtype. Conversely, the sarcomatoid and small cell cases were classified as basal/squamous or neuroendocrine-like, respectively. For cohort B, 50 (29%) of 173 cases had reported secondary variant histology. Cases with squamous variant had basal profiles, small cell cases expressed neuronal markers, and micropapillary cases were classified as luminal. Sarcomatoid tumors had robust epithelial-mesenchymal transition marker expression.

Conclusions: Our data suggest that in MIBC with secondary variant, the urothelial component can demonstrate an expression profile that closely resembles the variant component.
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http://dx.doi.org/10.1093/ajcp/aqab047DOI Listing
June 2021

Intravesical gemcitabine for non-muscle invasive bladder cancer.

Cochrane Database Syst Rev 2021 06 14;6:CD009294. Epub 2021 Jun 14.

Urology Section, Minneapolis VA Health Care System, Minneapolis, Minnesota, USA.

Background: It remains unclear whether people with non-muscle invasive bladder cancer (NMIBC) benefit from intravesical gemcitabine compared to other agents in the primary or recurrent setting following transurethral resection of a bladder tumor. This is an update of a Cochrane Review first published in 2012. Since that time, several randomized controlled trials (RCTs) have been reported, making this update relevant.  OBJECTIVES: To assess the comparative effectiveness and toxicity of intravesical gemcitabine instillation for NMIBC.

Search Methods: We performed a comprehensive literature search of the Cochrane Library, MEDLINE, Embase, four other databases, trial registries, and conference proceedings to 11 September 2020, with no restrictions on the language or status of publication.

Selection Criteria: We included RCTs in which participants received intravesical gemcitabine for primary or recurrent NMIBC.

Data Collection And Analysis: Two review authors independently assessed the included studies and extracted data for the primary outcomes: time to recurrence, time to progression, grade III to V adverse events determined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0), and the secondary outcomes: time to death from bladder cancer, time to death from any cause, grade I or II adverse events determined by the CTCAE v5.0 and disease-specific quality of life. We performed statistical analyses using a random-effects model and rated the certainty of the evidence using GRADE.

Main Results: We included seven studies with 1222 participants with NMIBC across five comparisons. This abstract focuses on the primary outcomes of the three most clinically relevant comparisons. 1. Gemcitabine versus saline: based on two years' to four years' follow-up, gemcitabine may reduce the risk of recurrence over time compared to saline (39% versus 47% recurrence rate, hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.54 to 1.09; studies = 2, participants = 734; I = 49%; low-certainty evidence), but the CI included the possibility of no effect.  Gemcitabine may result in little to no difference in the risk of progression over time compared to saline (4.6% versus 4.8% progression rate, HR 0.96, 95% CI 0.19 to 4.71; studies = 2, participants = 654; I = 53%; low-certainty evidence).  Gemcitabine may result in little to no difference in the CTCAE grade III to V adverse events compared to saline (5.9% versus 4.7% adverse events rate, risk ratio [RR] 1.26, 95% CI 0.58 to 2.75; studies = 2, participants = 668; I = 24%; low-certainty evidence).  2. Gemcitabine versus mitomycin: based on three years' follow-up (studies = 1, participants = 109), gemcitabine may reduce the risk of recurrence over time compared to mitomycin (17% versus 40% recurrence rate, HR 0.36, 95% CI 0.19 to 0.69; low-certainty evidence). Gemcitabine may reduce the risk of progression over time compared to mitomycin (11% versus  18% progression rate, HR 0.57, 95% CI 0.32 to 1.01; low-certainty evidence), but the CI included the possibility of no effect.  We are very uncertain about the effect of gemcitabine on the CTCAE grade III to V adverse events compared to mitomycin (RR 0.51, 95% CI 0.13 to 1.93; very low-certainty evidence). The analysis was only based on recurrent NMIBC. 3. Gemcitabine versus Bacillus Calmette-Guérin (BCG) for recurrent (one-course BCG failure) high-risk NMIBC: based on 6 months' to 22 months' follow-up (studies = 1, participants = 80), gemcitabine may reduce the risk of recurrence compared to BCG (41% versus 97% recurrence rate, HR 0.15, 95% CI 0.09 to 0.26; low-certainty evidence) and progression over time (16% versus 33% progression rate, HR 0.45, 95% CI 0.27 to 0.76; low-certainty evidence). We are very uncertain about the effect of gemcitabine on the CTCAE grade III to V adverse events compared to BCG (RR 1.00, 95% CI 0.21 to 4.66; very low-certainty evidence).  In addition, the review provides information on  the comparison of gemcitabine versus BCG and gemcitabine versus one-third dose BCG.  AUTHORS' CONCLUSIONS: Based on findings of this review, gemcitabine may have a more favorable impact on recurrence and progression-free survival than mitomycin but we are very uncertain as to how major adverse events compare. The same is true when comparing gemcitabine to BCG in individuals with high risk disease who have previously failed BCG. The underlying low- to very low-certainty evidence indicates that our confidence in these results is limited; the true effects may be substantially different from these findings; therefore, better quality studies are needed.
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http://dx.doi.org/10.1002/14651858.CD009294.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202966PMC
June 2021

Digest: On the contribution of phenotypic plasticity to adaptation in desert environments.

Authors:
Vikram P Narayan

Evolution 2021 Jun 30;75(6):1585-1586. Epub 2021 May 30.

The School of Biological Sciences, The University of Queensland, St. Lucia, Queensland, 4072, Australia.

How do organisms adapt to new environments, and what role does phenotypic plasticity play? Bittner et al. compared water consumption in laboratory-reared house mice derived from xeric and mesic populations and found evidence for adaptive phenotypic plasticity as well as genetic differences between populations.
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http://dx.doi.org/10.1111/evo.14267DOI Listing
June 2021

A Helpful Tool in the Renal Surgery Armamentarium: Dorsal Lumbotomy nephrectomy for Tumor in Patients with End-Stage Renal Disease.

Urology 2021 Mar 25. Epub 2021 Mar 25.

Department of Urology, Emory University, Atlanta, GA; Winship Cancer Institute, Emory University, Atlanta, GA. Electronic address:

Objective: To compare operative outcomes between the dorsal lumbotomy (DL) and laparoscopic nephrectomy (LN) approaches for patients with end stage renal disease (ESRD) undergoing nephrectomy. DL operative technique is also described.

Materials And Methods: We performed a retrospective review of all patients undergoing DL nephrectomy at Emory University from 2008-2020. Cases were matched with control patients with ESRD who had undergone LN. Parameters evaluated included operative time, estimated blood loss, length of stay, postoperative narcotic requirements, and complication rates. Statistical analysis performed with SPSS.

Results: 43 DL patients and 86 LN patients were assessed. DL had shorter total OR time (173min vs 198min; P = 0.001) and surgery time (101min vs 135min; P<0.001) compared to LN. There was a trend towards decreased mean length of stay among the DL group (2.65d vs 3.14d; P = 0.069) as well as daily narcotic requirement measured in oral morphine equivalents (54.8mg/day vs 73.6mg/day, P = 0.051). There were no differences in estimated blood loss, perioperative complication rates, ICU admissions, or 30-day readmissions. Limitations include retrospective design and small sample size.

Conclusion: Among patients with ESRD, DL was found to be safe and effective compared to LN, with shorter operative times, a trend towards decreased length of stay and post-operative narcotic requirements, and similar perioperative complication rates. DL should be considered as an approach for nephrectomy in this patient population.
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http://dx.doi.org/10.1016/j.urology.2021.03.008DOI Listing
March 2021

Sarcopenia and modified Glasgow Prognostic Score predict postsurgical outcomes in localized renal cell carcinoma.

Cancer 2021 Jun 24;127(12):1974-1983. Epub 2021 Mar 24.

Department of Urology, Emory University School of Medicine, Atlanta, Georgia.

Background: Body composition and inflammation are gaining importance for prognostication in cancer. This study investigated the individual and combined utility of the preoperative skeletal muscle index (SMI) and the modified Glasgow Prognostic Score (mGPS) for estimating postoperative outcomes in patients with localized renal cell carcinoma (RCC) undergoing nephrectomy.

Methods: The authors performed a retrospective review of 352 patients with localized RCC. SMI was measured via computed tomography or magnetic resonance imaging. Patients met the criteria for sarcopenia by body mass index- and sex-stratified thresholds. Multivariable and Kaplan-Meier analyses of associations of sarcopenia and mGPS with overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival (CSS) were performed. Variables were analyzed independently and combined into risk groups: low risk (nonsarcopenic, low mGPS), medium risk (sarcopenia only), medium risk (inflammation only), and high risk (sarcopenic, high mGPS). Receiver operating characteristic (ROC) curves were used to analyze risk groups in comparison with the Stage, Size, Grade, and Necrosis (SSIGN) score and the modified International Metastatic RCC Database Consortium (IMDC) score.

Results: The majority of the patients were at stage pT3 (63%), 39.5% of the patients were sarcopenic, and 19.3% had an elevated mGPS at the baseline. The median follow-up time was 30.4 months. Sarcopenia and mGPS were independently associated with worse OS (hazard ratio for sarcopenia, 1.64; P = .006; hazard ratio for mGPS, 1.72; P = .012), CSS, and RFS. Risk groups had an increasing association with worse RFS (P = .015) and CSS (P = .004) but not OS (P = .087). ROC analyses demonstrated a higher area under the curve for risk groups in comparison with the SSIGN and IMDC scores at 5 years.

Conclusions: Sarcopenia and an elevated mGPS were associated with worse clinical outcomes in this study of patients with localized RCC. This has implications for preoperative prognostication and treatment decision-making.

Lay Summary: Kidney cancer is a disease with a wide variety of outcomes. Among patients undergoing surgical removal of the kidney for cancer that has not spread beyond the kidney, many are cured, but some experience recurrence. Physicians are seeking ways to better predict who is at risk for recurrence or death from kidney cancer. This study has evaluated body composition and markers of inflammation before surgery to predict the risk of recurrence or death after surgery. Specifically, low muscle mass and an elevated inflammation score (the modified Glasgow Prognostic Score) have been associated with an increased likelihood of recurrence of kidney cancer and death.
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http://dx.doi.org/10.1002/cncr.33462DOI Listing
June 2021

Reply by Authors.

J Urol 2021 06 18;205(6):1620-1621. Epub 2021 Mar 18.

Department of Urology, University of Texas MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1097/JU.0000000000001633.03DOI Listing
June 2021

Editorial Comment.

Authors:
Vikram M Narayan

J Urol 2021 05 26;205(5):1351. Epub 2021 Feb 26.

Urologic Oncology, Emory University School of Medicine, Atlanta, Georgia.

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http://dx.doi.org/10.1097/JU.0000000000001559.01DOI Listing
May 2021

Oncologic Equipoise Between Robotic and Open Radical Cystectomy.

J Endourol 2021 Apr 16. Epub 2021 Apr 16.

Department of Urology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Our objective was to establish the incidence of positive surgical margins, recurrence patterns, and recurrence-free (RFS) and overall survival (OS) in a large cohort of patients undergoing robotic (robot-assisted radical cystectomy [RARC]) and open radical cystectomy (ORC). We performed a large retrospective cohort study at a high-volume academic tertiary referral center. Patients were those who underwent RC for bladder cancer from 2005 to 2017. Patients were allocated to ORC or RARC by patient and surgeon choice. Propensity matching and a multivariable analysis were performed to determine factors predictive of RFS and OS after RC. All analyses were done with SAS 9.4. The study included 1885 patients, 13.5% of whom underwent RARC. There was no difference in positive soft tissue surgical margins (2.4% in ORC and 1.2% in RARC). There were no differences in recurrence patterns, nor in the severity of pathology distribution between the two cohorts. Peritoneal carcinomatosis was seen in 1.1% of ORC and 0.8% in RARC. Shorter RFS was associated with younger age (hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.03-1.05,  < 0.001), neoadjuvant chemotherapy (HR 1.41, 95% CI 1.14-1.75,  = 0.002), higher pathologic stage (stage ≥T HR 2.45, 95% CI 1.91-3.16,  < 0.001), lymph node positivity at cystectomy (HR 1.92, 95% CI 1.50-2.47,  < 0.001), and positive surgical margins (HR 1.49, 95% CI 1.09-2.05,  = 0.01). RFS and OS did not differ by surgical approach (HR 1.04, 95% CI 0.83-1.30),  = 0.75 and (HR 0.89, 95% CI 0.67-1.19),  = 0.43, respectively. The data from this study support continued use of RARC as a safe oncologic procedure, with similar outcomes to ORC.
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http://dx.doi.org/10.1089/end.2020.0450DOI Listing
April 2021

Contemporary Outcomes of Patients with Nonmuscle-Invasive Bladder Cancer Treated with bacillus Calmette-Guérin: Implications for Clinical Trial Design.

J Urol 2021 06 27;205(6):1612-1621. Epub 2021 Jan 27.

Department of Urology, University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Recurrent disease after bacillus Calmette-Guérin treatment presents a therapeutic challenge. To aid trial development, the U.S. Food and Drug Administration defined "adequate bacillus Calmette-Guérin" therapy and adopted the "bacillus Calmette-Guérin unresponsive" disease state. Available data for efficacy benchmark comparison are outdated, leading to concerns about appropriate control arms and sample size calculations. We describe a contemporary cohort of patients with nonmuscle-invasive bladder cancer treated with intravesical bacillus Calmette-Guérin, and provide benchmark outcomes data.

Materials And Methods: We retrospectively reviewed patients receiving adequate bacillus Calmette-Guérin therapy at a tertiary cancer center between January 2004 and August 2018. Unadjusted univariable analysis was conducted using the Pearson chi-square test. Kaplan-Meier estimates for recurrence-free survival-high grade, progression-free survival-muscle-invasive bladder cancer and overall survival were used to create survival curves and compared using the log-rank test.

Results: Of the 542 patients who received adequate bacillus Calmette-Guérin, 518 (90%) had European Association Urology high risk disease, with carcinoma in situ present in 175 (32%). With a median followup of 47.8 months, freedom from high grade recurrence at 1, 3 and 5 years was 81%, 76% and 74%, respectively, and progression-free survival was 97%, 93% and 92%. Progression to muscle invasion at 5 years was exclusively seen in patients with high risk disease (progression-free survival 91%; log-rank test, p=0.024).

Conclusions: A contemporary cohort of patients with nonmuscle-invasive bladder cancer treated with adequate bacillus Calmette-Guérin demonstrated markedly better outcomes than seen in prior studies. These data could be used in the design of clinical trials, to guide power calculations, as well as serve as benchmarks for comparison to evaluate nonrandomized studies.
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http://dx.doi.org/10.1097/JU.0000000000001633DOI Listing
June 2021

Prostatic arterial embolization for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia.

Cochrane Database Syst Rev 2020 12 19;12:CD012867. Epub 2020 Dec 19.

Department of Urology, University of Minnesota, Minneapolis, Minnesota, USA.

Background: A variety of minimally invasive surgical approaches are available as an alternative to transurethral resection of the prostate (TURP) for management of lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH). Prostatic arterial embolization (PAE) is a relatively new, minimally invasive treatment approach.

Objectives: To assess the effects of PAE compared to other procedures for treatment of LUTS in men with BPH.

Search Methods: We performed a comprehensive search using multiple databases (The Cochrane Library, MEDLINE, Embase, LILACS, Scopus, Web of Science, and Google Scholar), trials registries, other sources of grey literature, and conference proceedings with no restrictions on language of publication or publication status, up until 25 September 2020.

Selection Criteria: We included parallel-group randomized controlled trials (RCTs), as well as non-randomized studies (NRS, limited to prospective cohort studies with concurrent comparison groups) enrolling men over the age of 40 with LUTS attributed to BPH undergoing PAE versus TURP or other surgical interventions.  DATA COLLECTION AND ANALYSIS: Two review authors independently classified studies for inclusion or exclusion and abstracted data from the included studies. We performed statistical analyses by using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We used GRADE guidance to rate the certainty of evidence of RCTs and NRSs.  MAIN RESULTS: We found data to inform two comparisons: PAE versus TURP (six RCTs and two NRSs), and PAE versus sham (one RCT). Mean age, IPSS, and prostate volume of participants were 66 years, 22.8, and 72.8 mL, respectively. This abstract focuses on the comparison of PAE versus TURP as the primary topic of interest. PAE versus TURP We included six RCTs and two NRSs with short-term (up to 12 months) follow-up and one RCT with long-term follow-up (13 to 24 months).  Short-term follow-up: based on RCT evidence, there may be little to no difference in urologic symptom score improvement (mean difference [MD] 1.55, 95% confidence interval [CI] -0.40 to 3.50; 369 participants; 6 RCTs; I² = 75%; low-certainty evidence) measured by the International Prostatic Symptom Score (IPSS) on a scale from 0 to 35, with higher scores indicating worse symptoms. There may be little to no difference in quality of life (MD 0.16, 95% CI -0.37 to 0.68; 309 participants; 5 RCTs; I² = 56%; low-certainty evidence) as measured by the IPSS quality of life question on a scale from 0 to 6, with higher scores indicating worse quality of life between PAE and TURP, respectively. While we are very uncertain about the effects of PAE on major adverse events (risk ratio [RR] 0.71, 95% CI 0.16 to 3.10; 250 participants; 4 RCTs; I² = 26%; very low-certainty evidence), PAE may increase re-treatments (RR 3.64, 95% CI 1.02 to 12.98; 204 participants; 3 RCTs; I² = 0%; low-certainty evidence). Based on 18 re-treatments per 1000 men in the TURP group, this corresponds to 47 more (0 more to 214 more) per 1000 men undergoing PAE.   We are very uncertain about the effects on erectile function (MD -0.03, 95% CI -6.35 to 6.29; 129 participants; 2 RCTs; I² = 78%; very low-certainty evidence) measured by the International Index of Erectile Function at 5 on a scale from 1 to 25, with higher scores indicating better function. NRS evidence when available yielded similar results. Based on evidence from NRS, PAE may reduce the occurrence of ejaculatory disorders (RR 0.51, 95% CI 0.35 to 0.73; 260 participants; 1 NRS; low-certainty evidence). Longer-term follow-up: based on RCT evidence, we are very uncertain about the effects of PAE on urologic symptom scores (MD 0.30, 95% CI -3.17 to 3.77; 95 participants; very low-certainty evidence) compared to TURP. Quality of life may be similar (MD 0.20, 95% CI -0.49 to 0.89; 95 participants; low-certainty evidence). We are also very uncertain about major adverse events (RR 1.96, 95% CI 0.63 to 6.13; 107 participants; very low-certainty evidence). We did not find evidence on erectile function and ejaculatory disorders. Based on evidence from NRS, PAE may increase re-treatment rates (RR 1.51, 95% CI 0.43 to 5.29; 305 participants; low-certainty evidence); based on 56 re-treatments per 1000 men in the TURP group. this corresponds to 143 more (25 more to 430 more) per 1000 men in the PAE group.  AUTHORS' CONCLUSIONS: Compared to TURP up to 12 months (short-term follow-up), PAE may provide similar improvement in urologic symptom scores and quality of life. While we are very uncertain about major adverse events, PAE may increase re-treatment rates. We are uncertain about erectile function, but PAE may reduce ejaculatory disorders. Longer term (follow-up of 13 to 24 months), we are very uncertain as to how both procedures compare with regard to urologic symptom scores, but quality of life appears to be similar. We are very uncertain about major adverse events but PAE may increase re-treatments. We did not find longer term evidence on erectile function and ejaculatory disorders. Certainty of evidence for the main outcomes of this review was low or very low, signalling that our confidence in the reported effect size is limited or very limited, and that this topic should be better informed by future research.
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http://dx.doi.org/10.1002/14651858.CD012867.pub2DOI Listing
December 2020

Digest: Sexually selected weapons: Winning the fight, but losing the war for reproduction on a changing battlefield.

Authors:
Vikram P Narayan

Evolution 2021 Feb 25;75(2):559-560. Epub 2020 Dec 25.

The School of Biological Sciences, The University of Queensland, Saint Lucia, Queensland, Australia.

What conditions favor the evolution of large animal weapons? In the Japanese rhinoceros beetle, Trypoxylus dichotomus, del Sol et al. found that selection favors large horns in populations where males compete over guardianship of scarce female feeding territories. However, in other populations, an abundance of female feeding territories reduces the chance of mating success for these guarding males, leading to the evolution of relatively shorter horn sizes. This finding illustrates that female habitat and resource use have the potential to influence evolution of male weapon size through sexual selection.
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http://dx.doi.org/10.1111/evo.14145DOI Listing
February 2021

Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.

Lancet Oncol 2021 01 27;22(1):107-117. Epub 2020 Nov 27.

Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Background: BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer.

Methods: In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 10 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849.

Findings: Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths.

Interpretation: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state.

Funding: FKD Therapies Oy.
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http://dx.doi.org/10.1016/S1470-2045(20)30540-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988888PMC
January 2021

The role of the urologist, BCG vaccine administration, and SARS-CoV-2: An overview.

BJUI Compass 2020 Jul 22;1(3):87-92. Epub 2020 Jun 22.

Department of Urology The University of Texas MD Anderson Cancer Center Houston TX USA.

Objectives: To summarize the available literature regarding bacillus Calmette-Guerin (BCG) administration, severe acute respiratory syndrome conoravirus-2 (SARS-CoV-2), and the resulting clinical condition coronavirus disease (COVID-19) in light of recent epidemiologic work suggesting decreased infection severity in BCG immunized populations while highlighting the potential role of the urologist in clinical trials and ongoing research efforts.

Materials And Methods: We reviewed the available literature regarding COVID-19 and BCG vaccination. Specifically, the epidemiologic evidence for decreased COVID-19 morbidity in countries with BCG vaccination programs, current clinical trials for BCG vaccination to protect against COVID-19, potential mechanisms and rationale for this protection, and the role of the urologist and urology clinic in providing support and/or leading ongoing efforts.

Results: Epidemiologic evidence suggests that the crude case fatality rates are lower for countries with BCG vaccination compared to those without such programs. Four prospective, randomized clinical trials for BCG vaccination were identified including NCT04348370 (BADAS), NCT04327206 (BRACE), NCT04328441 (BCG-CORONA), and NCT04350931. BCG administration may contribute to innate and adaptive immune priming with several opportunities for translational research.

Conclusions: The urologist's expertise with BCG and the infrastructure of urologic clinics may afford several opportunities for collaboration and leadership to evaluate and understand the potential role of BCG in the current COVID-19 pandemic.
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http://dx.doi.org/10.1002/bco2.21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361196PMC
July 2020

TCF21 Promotes Luminal-Like Differentiation and Suppresses Metastasis in Bladder Cancer.

Mol Cancer Res 2020 06 2;18(6):811-821. Epub 2020 Mar 2.

Department of Urology, University of Texas MD Anderson Cancer Center, Houston, Texas.

Little is known regarding the subclone evolution process in advanced bladder cancer, particularly with respect to the genomic alterations that lead to the development of metastatic lesions. In this project, we identify gene expression signatures associated with metastatic bladder cancer through mRNA expression profiling of RNA isolated from 33 primary bladder cancer and corresponding lymph node (LN) metastasis samples. Gene expression profiling (GEP) was performed on RNA isolated using the Illumina DASL platform. We identified the developmental transcription factor TCF21 as being significantly higher in primary bladder cancer compared with LN metastasis samples. To elucidate its function in bladder cancer, loss- and gain-of-function experiments were conducted in bladder cancer cell lines with high and low expression of TCF21, respectively. We also performed GEP in bladder cancer cell lines following TCF21 overexpression. We identified 2,390 genes differentially expressed in primary bladder cancer and corresponding LN metastasis pairs at an FDR cutoff of 0.1 and a fold change of 1. Among those significantly altered, expression of TCF21 was higher in the primary tumor compared with LN metastasis. We validated this finding with qPCR and IHC on patient samples. Moreover, TCF21 expression was higher in luminal cell lines and knockdown of TCF21 increased invasion, tumor cell dissemination, and metastasis. In contrast, overexpression of TCF21 in highly metastatic basal bladder cancer cell lines decreased their invasive and metastatic potential. IMPLICATIONS: TCF21 is differentially overexpressed in primary bladder cancer compared with matched LN metastasis, with and studies demonstrating a metastasis suppressor function of this transcription factor.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0766DOI Listing
June 2020

Probing Pedomorphy and Prolonged Lifespan in Naked Mole-Rats and Dwarf Mice.

Physiology (Bethesda) 2020 03;35(2):96-111

Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota.

Pedomorphy, maintenance of juvenile traits throughout life, is most pronounced in extraordinarily long-lived naked mole-rats. Many of these traits (e.g., slow growth rates, low hormone levels, and delayed sexual maturity) are shared with spontaneously mutated, long-lived dwarf mice. Although some youthful traits likely evolved as adaptations to subterranean habitats (e.g., thermolability), the nature of these intrinsic pedomorphic features may also contribute to their prolonged youthfulness, longevity, and healthspan.
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http://dx.doi.org/10.1152/physiol.00032.2019DOI Listing
March 2020

Radical cystectomy in women: Impact of the robot-assisted versus open approach on surgical outcomes.

Urol Oncol 2020 04 14;38(4):247-254. Epub 2020 Jan 14.

Department of Urology, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Objectives: To perform a comparison of complications following open versus robot-assisted radical cystectomy (RC) among women who undergo the procedure. Studies comparing robotic to open RC have been mixed without a clear delineation of which patients benefit the most from one modality vs. the other, leading to continued debate.

Patients And Methods: This was a retrospective study of women who underwent either open or robotic RC at the MD Anderson Cancer Center from 1/2014 to 6/2018. Co-morbidities, pathologic data, and complications were assessed with descriptive statistics, along with uni- and multivariable logistic regression.

Results: 122 women underwent either open (n = 76) or robotic (n = 46) RC. Open RC was associated with greater intraoperative blood loss (median EBL 775 ml vs. 300 ml, P < 0.001). In both uni- and multivariable analyses, open RC was associated with a greater odds of intraoperative transfusion compared to robotic RC (odds ratio 6.49, 95% CI 2.85-14.78, P < 0.001). Women undergoing open RC were also at greater odds of receiving 4 or more units of packed red blood cells (odds ratio 5.46 (1.75-17.02), P = 0.003). Robotic RC conferred a higher median lymph node yield (27 vs. 20 nodes, P, <0.001) and operative times (median 513 min vs. 391.5 min, P < 0.001). There were no differences in margin positivity, length of stay, or readmission rates at 30 and 90 days.

Conclusions: Robotic RC was associated with a significantly lower risk of transfusion and EBL, and a higher median lymph node yield and operative time. Unique anatomic considerations may in part be responsible for these findings.
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http://dx.doi.org/10.1016/j.urolonc.2019.12.005DOI Listing
April 2020

Intravesical Gene Therapy.

Urol Clin North Am 2020 Feb;47(1):93-101

University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1373, Houston, TX 77030, USA. Electronic address:

Non-muscle-invasive bladder cancer is a challenging disease to treat, with few effective salvage intravesical options available for patients who develop bacillus Calmette-Guerin-unresponsive disease. Although radical cystectomy with pelvic lymphadenectomy remains the gold standard treatment for these patients, there remains an unmet need for other options for those who are unable or unwilling to undergo surgery. To this end, intravesical gene therapy is emerging as a potential alternative with promising early data and ongoing efforts to better understand the mechanisms of action to optimize therapy.
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http://dx.doi.org/10.1016/j.ucl.2019.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986363PMC
February 2020

Bacillus Calmette-Guérin Salvage Therapy: Definitions and Context.

Urol Clin North Am 2020 Feb;47(1):1-4

Department of Urology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1373, Houston, TX 77030, USA.

High-risk non-muscle invasive bladder cancer is marked by frequent disease recurrences and risk of stage progression, contributing to high surveillance, treatment-related costs, and patient anxiety. Although the mainstay of high-risk non-muscle invasive bladder cancer clinical management remains transurethral resection followed by intravesical bacillus Calmette-Guérin (BCG), patients who develop BCG-unresponsive disease have few salvage options outside of a radical cystectomy with pelvic lymphadenectomy. This article provides a historical context relevant to the development of the BCG-unresponsive definition, an overview of current clinical trial expectations, and an introduction to this issue of Urologic Clinics.
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http://dx.doi.org/10.1016/j.ucl.2019.09.002DOI Listing
February 2020

Quality of Intervention Reporting in Randomized Clinical Trials Published in Urology Journals.

Eur Urol 2020 03 14;77(3):296-298. Epub 2019 Nov 14.

Oklahoma State University Center for Health Sciences, Tulsa, OK, USA.

We used the Template for Intervention Description and Replication (TIDieR) to find evidence that intervention reporting in urology randomized controlled trials is suboptimal. Action to improve intervention reporting is warranted and we advise extending TIDieR into Consolidated Standards for Reporting Trials guidelines.
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http://dx.doi.org/10.1016/j.eururo.2019.10.029DOI Listing
March 2020

The future of clinical trials in urological oncology.

Nat Rev Urol 2019 12 11;16(12):722-733. Epub 2019 Oct 11.

Minneapolis VA Medical Center and University of Minnesota Department of Urology, Minneapolis, MN, 55417, USA.

Well-designed clinical trials in urological oncology help to guide treatment decisions and aid in counselling patients, ultimately serving to improve outcomes. Since the term evidence-based medicine was first used by Gordon Guyatt in 1991, a renewed emphasis on methodology, transparent trial design and study reporting has helped to improve clinical research and in turn, the landscape of medical literature. Novel clinical trial designs (including multi-arm, multistage trials, basket and umbrella studies and research from big data sources, such as electronic health records, administrative claims databases and quality monitoring registries) are well suited to advance innovation in urological oncology. Existing urological clinical trials are often limited by small numbers, are statistically underpowered and many face difficulties with accrual. Thus, efforts to improve trial design are of considerable importance. The development and use of standard outcome sets and adherence to reporting guidelines offer researchers the opportunity to guide value-oriented care, minimize research waste and efficiently identify solutions to the unanswered questions in urology cancer care.
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http://dx.doi.org/10.1038/s41585-019-0243-xDOI Listing
December 2019

The Role of Surgery in Initially Metastatic Urothelial Carcinoma: Informing a Definitive Trial.

Eur Urol Oncol 2020 02 6;3(1):102-103. Epub 2019 Sep 6.

Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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http://dx.doi.org/10.1016/j.euo.2019.08.006DOI Listing
February 2020

Autonomous Development of Active Binocular and Motion Vision Through Active Efficient Coding.

Front Neurorobot 2019 16;13:49. Epub 2019 Jul 16.

Frankfurt Institute for Advanced Studies, Frankfurt, Germany.

We present a model for the autonomous and simultaneous learning of active binocular and motion vision. The model is based on the Active Efficient Coding (AEC) framework, a recent generalization of classic efficient coding theories to active perception. The model learns how to efficiently encode the incoming visual signals generated by an object moving in 3-D through sparse coding. Simultaneously, it learns how to produce eye movements that further improve the efficiency of the sensory coding. This learning is driven by an intrinsic motivation to maximize the system's coding efficiency. We test our approach on the humanoid robot iCub using simulations. The model demonstrates self-calibration of accurate object fixation and tracking of moving objects. Our results show that the model keeps improving until it hits physical constraints such as camera or motor resolution, or limits on its internal coding capacity. Furthermore, we show that the emerging sensory tuning properties are in line with results on disparity, motion, and motion-in-depth tuning in the visual cortex of mammals. The model suggests that vergence and tracking eye movements can be viewed as fundamentally having the same objective of maximizing the coding efficiency of the visual system and that they can be learned and calibrated jointly through AEC.
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http://dx.doi.org/10.3389/fnbot.2019.00049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646586PMC
July 2019

Genomic Analysis and Treatment Response of a Bladder Urothelial Carcinoma With Sarcomatoid Variant Histology.

Clin Genitourin Cancer 2019 10 25;17(5):e888-e892. Epub 2019 May 25.

Department of Urology, University of Minnesota, Minneapolis, MN.

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http://dx.doi.org/10.1016/j.clgc.2019.05.019DOI Listing
October 2019

Prostatic urethral lift for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia.

Cochrane Database Syst Rev 2019 05 25;5:CD012832. Epub 2019 May 25.

Department of Urology, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon, Korea, South, 26426.

Background: A variety of minimally invasive surgical approaches are available as an alternative to transurethral resection of prostate (TURP) for the management of lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH). A recent addition to these is prostatic urethral lift (PUL).

Objectives: To assess the effects of PUL for the treatment of LUTS in men with BPH.

Search Methods: We performed a comprehensive search of multiple databases (the Cochrane Library, MEDLINE, Embase, LILACS, Scopus, Web of Science, and Google Scholar), trials registries, other sources of grey literature, and conference proceedings with no restrictions on the language of publication or publication status up until 31 January 2019.

Selection Criteria: We included parallel group randomized controlled trials (RCTs). While we planned to include non-RCTs if RCTs had provided low-certainty evidence for a given outcome and comparison, we could not find any non-RCTs.

Data Collection And Analysis: Two review authors independently screened the literature, extracted data, and assessed risk of bias. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We planned subgroup analyses by age, prostate volume, and severity of baseline symptoms. We used the GRADE approach to rate the certainty of the evidence.

Main Results: We included two RCTs with 297 participants comparing PUL to sham surgery or TURP. The mean age was 65.6 years and mean International Prostate Symptom Score was 22.7. Mean prostate volume was 42.2 mL. We considered review outcomes measured up to and including 12 months after randomization as short-term and later than 12 months as long-term. For patient-reported outcomes, lower scores indicate more urological symptom improvement and higher quality of life. In contrast, higher scores refers to better erectile and ejaculatory function.PUL versus sham: based on one study of 206 randomized participants with short follow-up (up to three months), PUL may lead to a clinically important improvement in urological symptom scores (mean difference (MD) -5.20, 95% confidence interval (CI) -7.44 to -2.96; low-certainty evidence) and likely improves quality of life (MD -1.20, 95% CI -1.67 to -0.73; moderate-certainty evidence). We are uncertain whether PUL increases major adverse events (very low-certainty evidence). There were no retreatments reported in either study group by three months. PUL likely results in little to no difference in erectile function (MD -1.40, 95% CI -3.24 to 0.44; moderate-certainty evidence) and ejaculatory function (MD 0.50, 95% CI -0.38 to 1.38; moderate-certainty evidence).PUL versus TURP: based on one study of 91 randomized participants with a short follow-up (up to 12 months), PUL may result in a substantially lesser improvement in urological symptom scores than TURP (MD 4.50, 95% CI 1.10 to 7.90; low-certainty evidence). PUL may result in a slightly reduced or similar quality of life (MD 0.30, 95% CI -0.49 to 1.09; low-certainty evidence). We are very uncertain whether PUL may cause fewer major adverse events but increased retreatments (both very low-certainty evidence). PUL probably results in little to no difference in erectile function (MD 0.80, 95% CI -1.50 to 3.10; moderate-certainty evidence), but probably results in substantially better ejaculatory function (MD 5.00, 95% CI 3.08 to 6.92; moderate-certainty evidence).With regards to longer term follow-up (up to 24 months) based on one study of 91 randomized participants, PUL may result in a substantially lesser improvement in urological symptom score (MD 6.10, 95% CI 2.16 to 10.04; low-certainty evidence) and result in little worse to no difference in quality of life (MD 0.80, 95% CI 0.00 to 1.60; low-certainty evidence). The study did not report on major adverse events. We are very uncertain whether PUL increases retreatment (very low-certainty evidence). PUL likely results in little to no difference in erectile function (MD 1.60, 95% CI -0.80 to 4.00; moderate-certainty evidence), but may result in substantially better ejaculatory function (MD 4.30, 95% CI 2.17 to 6.43; low-certainty evidence).We were unable to perform any of the predefined secondary analyses for either comparison.We found no evidence for other comparisons such as PUL versus laser ablation or enucleation.

Authors' Conclusions: PUL appears less effective than TURP in improving urological symptoms both short-term and long term, while quality of life outcomes may be similar. The effect on erectile function appears similar but ejaculatory function may be better. We are uncertain about major adverse events short-term and found no long-term information. We are very uncertain about retreatment rates both short-term and long-term. We were unable to assess the effects of PUL in subgroups based on age, prostate size, or symptom severity and also could not assess how PUL compared to other surgical management approaches. Given the large numbers of alternative treatment modalities to treat men with LUTS secondary to BPH, this represents important information that should be shared with men considering surgical treatment.
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http://dx.doi.org/10.1002/14651858.CD012832.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535104PMC
May 2019

A critical appraisal of biomarkers in prostate cancer.

Authors:
Vikram M Narayan

World J Urol 2020 Mar 16;38(3):547-554. Epub 2019 Apr 16.

Department of Urology, University of Minnesota, 420 Delaware Street SE, MMC 394, Minneapolis, MN, 55455, USA.

Purpose: A number of urine and blood-based biomarker tests have been described for prostate cancer, although to date there has only been a limited exploration of the methodology behind the validation studies that underpin these tests.

Methods: In this review, a selection of commercially available urine and blood-based biomarker tests for prostate cancer are described, and the underlying key validation studies for each test are critically appraised using the Standards for Reporting Diagnostic Accuracy (STARD) 2015 statement.

Results: The ExoDx Prostate Intelliscore, SelectMDx, Progensa PCA3, Mi-Prostate Score, 4K Score, and Prostate Health Index (PHI) tests were reviewed. Most of the validation studies supporting these tests perform exploratory analyses to determine cut-off values in a post hoc manner, comprise cohorts that are primarily Caucasian, report receiver operating characteristic curves that combine the biomarker's result with established clinical nomograms and are based on a reference standard (prostate biopsy) that lacks central pathology review. Deficiencies in STARD reporting guidelines include frequent failure to provide a published study protocol, prospective study registration in a registry, a flow diagram, justification for sample size determination, a discussion of adverse events with testing, and information on how missing or indeterminate test results should be managed.

Conclusions: Key validation studies that support many commercially available urine and blood-based biomarkers for prostate cancers have deficiencies in transparency based on STARD reporting guidelines, and limitations in methodology must be considered when deciding when these tests should be applied in clinical practice.
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http://dx.doi.org/10.1007/s00345-019-02759-xDOI Listing
March 2020

Re: Impact of Immune and Stromal Infiltration on Outcomes Following Bladder-sparing Trimodality Therapy for Muscle-invasive Bladder Cancer.

Eur Urol 2019 06 2;75(6):1034-1035. Epub 2019 Mar 2.

University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2019.02.022DOI Listing
June 2019

Clinical and Genomic Considerations for Variant Histology in Bladder Cancer.

Curr Oncol Rep 2019 02 26;21(3):23. Epub 2019 Feb 26.

Department of Urology, Division of Surgery, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1373, Houston, TX, 77030, USA.

Purpose Of Review: Urothelial carcinoma demonstrates remarkable plasticity in its ability to differentiate into divergent histologic subtypes in both a pure and mixed form. This review presents the most current data pertaining to bladder cancer with variant histology.

Recent Findings: Recognition of bladder cancer variants has increased profoundly in the past two decades with their inclusion in the pathologic guidelines and increased awareness among pathologists and urologists. Most of the available literature consists of small single-institutional studies, but there is compelling evidence to support deviation from the normal urothelial carcinoma management pathways for certain subtypes. While traditionally diagnosed by microscopic appearance, next-generation sequencing and molecular profiling have enabled identification of genomic markers associated with specific variants that exist in tumors lacking classic histologic hallmarks. This genomic information holds promise for predicting response to specific treatments or even in the development of novel targeted therapies. Combining increased awareness of variant histology, its impact on clinical outcomes, and genomic data will result in a more nuanced treatment approach to reduce morbidity and optimize oncologic outcomes for our patients.
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http://dx.doi.org/10.1007/s11912-019-0772-8DOI Listing
February 2019