Can MRI Help Inform Which Men With a History of Multifocal High-Grade Prostatic Intraepithelial Neoplasia or Atypical Small Acinar Proliferation Remain at an Elevated Risk for Clinically Significant Prostate Cancer?

PURPOSE: We investigated the association of MRI findings in men with a previous diagnosis of atypical small acinar proliferation (ASAP) or multifocal high-grade intraepithelial neoplasia (HGPIN) with pathologic findings on repeat biopsy. MATERIALS AND METHODS: We retrospectively reviewed patients with ASAP/multifocal HGPIN undergoing a repeat biopsy in the Michigan Urological Surgery Improvement Collaborative registry. We included men with and without an MRI after the index biopsy demonstrating ASAP/multifocal HGPIN but before the repeat biopsy. Men with an MRI prior to the index biopsy were excluded. We compared the proportion of men with ≥ GG2 CaP (Grade Group 2 prostate cancer) on repeat biopsy among the following groups with the χ2 test: no MRI, PIRADS (Prostate Imaging-Reporting and Data System) ≥ 4, and PIRADS ≤ 3. Multivariable models were used to estimate the adjusted association between MRI findings and ≥ GG2 CaP on repeat biopsy. RESULTS: Among the 207 men with a previous diagnosis of ASAP/multifocal HGPIN that underwent a repeat biopsy, men with a PIRADS ≥ 4 lesion had a higher proportion of ≥ GG2 CaP (56%) compared with men without an MRI (12%, P < .001). A lower proportion of men with PIRADS ≤ 3 lesions had ≥ GG2 CaP (3.0%) compared with men without an MRI (12%, P = .13). In the adjusted model, men with a PIRADS 4 to 5 lesion had higher odds (OR: 11.4, P < .001) of ≥ GG2 CaP on repeat biopsy. CONCLUSIONS: MRI is a valuable diagnostic tool to triage which men with a history of ASAP or multifocal HGPIN on initial biopsy should undergo or avoid repeat biopsy without missing clinically significant CaP.

Conversion to Radical Nephrectomy From Robotic Partial Nephrectomy Is Most Commonly Due to Anatomic and Oncologic Complexity.

PURPOSE: Partial nephrectomy is standard-of-care treatment for small renal masses. As utilization of partial nephrectomy increases and includes larger and complex tumors, the risk of conversion to radical nephrectomy likely increases. We evaluated incidence and reason for conversion to radical nephrectomy in patients scheduled for partial nephrectomy by surgeons participating in MUSIC (the Michigan Urologic Surgery Improvement Collaborative). MATERIALS AND METHODS: All patients in whom robotic partial nephrectomy was planned were stratified by completed procedure (robotic partial nephrectomy vs radical nephrectomy). Preoperative and intraoperative records were reviewed for preoperative assessment of difficulty and reason for conversion. Patient, tumor, pathologic, and practice variables were compared between cohorts. RESULTS: Of 650 patients scheduled for robotic partial nephrectomy, conversion to radical nephrectomy occurred in 27 (4.2%) patients. No conversions to open were reported. Preoperative documentation indicated a plan for possible conversion in 18 (67%) patients including partial with possible radical (n = 8), partial vs radical (n = 6), or likely radical nephrectomy (n = 4). Intraoperative documentation indicated that only 5 (19%) conversions were secondary to bleeding, with the remaining conversions due to tumor complexity and/or oncologic concerns. Patients undergoing conversion had larger (4.7 vs 2.8 cm, P < .001) and higher-complexity tumors (64% vs 6%, P < .001) with R.E.N.A.L. (for radius, exophytic/endophytic, nearness of tumor to collecting system, anterior/posterior, location relative to polar line) nephrometry score ≥ 10. The converted cases had a higher rate of ≥ pT3 (27% vs 8.4%, P = .008). CONCLUSIONS: There was a low rate of conversion from robotic partial to radical nephrectomy in the MUSIC-KIDNEY (Kidney mass: Identifying and Defining Necessary Evaluation and therapY) collaborative, and an even lower risk of conversion due to uncontrolled bleeding. Targeted review of each conversion identified appropriate decision-making based on oncologic risk in most cases.

Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial.

PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

Safety and Efficacy of a Composite Lipid Emulsion with Fish Oil in Hospitalized Neonates and Infants Requiring Prolonged Parenteral Nutrition - A Randomized, Double-Blind, Multicenter, Controlled Trial.

BACKGROUND: Intravenous lipids are critical to the care of extremely premature and other high-risk infants. OBJECTIVES: This study evaluated safety and efficacy of parenteral nutrition (PN) with composite intravenous lipid emulsion (CO-ILE) with fish oil compared with pure soybean oil lipid emulsion (SOLE). METHODS: Randomized, controlled, double-blind, multicenter study (NCT02579265) in neonates/infants anticipated to require ≥28 d of PN due to gastrointestinal malformations or injury. Duration of the initial and extended treatment phase was 28 d and 84 d, respectively (for patients with PN indication after day 28). RESULTS: Eighty-three patients (mean postnatal age 11.4 d, 54 preterm) received CO-ILE and 78 patients received SOLE (mean postnatal age 8.3 d, 59 preterm). Thirty-three patients per group completed 28 d of treatment. Risk of having conjugated bilirubin values >2 mg/dL confirmed by a second sample 7 d after the first during the initial treatment phase (primary outcome) was 2.4% (2 of 83) with CO-ILE and 3.8% (3 of 78) with SOLE (risk ratio: 0.59; 95% confidence interval [CI]: 0.09, 3.76). Between days 29 and 84, the number of patients with confirmed conjugated bilirubin values >2 mg/dL did not increase in the CO-ILE group (n = 2) and increased in the SOLE group (n = 9). At the end of the initial treatment phase, conjugated bilirubin concentrations were 45.6% lower under CO-ILE than under SOLE (P = 0.006). There was no clinical or laboratory evidence of essential fatty acid deficiency in patients in the CO-ILE group. Median time to discharge alive was 56.7 d and 66.4 d with CO-ILE and SOLE, respectively (hazard ratio: 1.16; 95% CI: 0.81, 1.68). CONCLUSIONS: CO-ILE was associated with a possible lower risk of cholestasis and significantly lower conjugated bilirubin concentration at the end of the initial treatment phase in high-risk neonates and infants as compared with patients treated with SOLE. In summary, these data indicate that CO-ILE can be considered safe and may be preferable over SOLE in high-risk neonates. This trial was registered at clinicaltrials.gov as NCT02579265.

Stage 1 and 2 Palliation: Comparing Ductal Stenting and Aorto-Pulmonary Shunts in Single Ventricles with Duct-Dependent Pulmonary Blood Flow.

Patent ductus arteriosus stenting (PDAS) for ductal-dependent pulmonary blood flow (DDPBF) provides a new paradigm for managing neonates with single ventricles (SV). Currently, sparse data exist regarding outcomes for subsequent palliation. We describe our experience with inter-stage care and stage 2 (S2P) conversion with PDAS in comparison to a prior era of patients who received surgical aorto-pulmonary shunts (APS). Retrospective review of 18 consecutive DDPBF SV patients treated with PDAS between 2016 and 2021 was done and compared with 9 who underwent APS from 2010 to 2016. Patient outcomes and pulmonary artery (PA) growth were analyzed. S2P was completed in all 18 with PDAS with no cardiac arrests and one post-S2P mortality. In the 9 APS patients, there was one cardiac arrest requiring ECMO and one mortality inter-stage. Off cardiopulmonary bypass strategy was utilized in 10/18 in the PDAS and 1/9 in the APS group (p = 0.005) at S2P. Shorter ventilation time, earlier PO feeding, and shorter hospital stay were noted in the PDAS group (p = 0.01, p = 0.006, p = 0.03) (S2P). Median Nakata index increase inter-stage was not significant between the PDAS and APS at 94.1 mm2/m2 versus 71.7 mm2/m2 (p = 0.94). Median change in pulmonary artery symmetry (PAS) was - 0.02 and - 0.24, respectively, which was statistically significant (p = 0.008). Neurodevelopmental outcomes were better in the PDAS group compared to the APS group (p = 0.02). PDAS provides excellent PA growth, inter-stage survival, progression along multistage single-ventricle palliation, and potentially improved neurodevelopmental outcomes. Most patients can be transitioned through 2 stages of palliation without CPB.

Technical development and validation of a clinically applicable microenvironment classifier as a biomarker of tumour hypoxia for soft tissue sarcoma.

BACKGROUND: Soft tissue sarcomas (STS) are rare, heterogeneous tumours and biomarkers are needed to inform management. We previously derived a prognostic tumour microenvironment classifier (24-gene hypoxia signature). Here, we developed/validated an assay for clinical application. METHODS: Technical performance of targeted assays (Taqman low-density array, nanoString) was compared in 28 prospectively collected formalin-fixed, paraffin-embedded (FFPE) biopsies. The nanoString assay was biologically validated by comparing to HIF-1α/CAIX immunohistochemistry (IHC) in clinical samples. The Manchester (n = 165) and VORTEX Phase III trial (n = 203) cohorts were used for clinical validation. The primary outcome was overall survival (OS). RESULTS: Both assays demonstrated excellent reproducibility. The nanoString assay detected upregulation of the 24-gene signature under hypoxia in vitro, and 16/24 hypoxia genes were upregulated in tumours with high CAIX expression in vivo. Patients with hypoxia-high tumours had worse OS in the Manchester (HR 3.05, 95% CI 1.54-5.19, P = 0.0005) and VORTEX (HR 2.13, 95% CI 1.19-3.77, P = 0.009) cohorts. In the combined cohort, it was independently prognostic for OS (HR 2.24, 95% CI 1.42-3.53, P = 0.00096) and associated with worse local recurrence-free survival (HR 2.17, 95% CI 1.01-4.68, P = 0.04). CONCLUSIONS: This study comprehensively validates a microenvironment classifier befitting FFPE STS biopsies. Future uses include: (1) selecting high-risk patients for perioperative chemotherapy; and (2) biomarker-driven trials of hypoxia-targeted therapies.

The Use and Short-term Outcomes of Active Surveillance in Men With National Comprehensive Cancer Network Favorable Intermediate-risk Prostate Cancer: The Initial Michigan Urological Surgery Improvement Collaborative Experience.

PURPOSE: National Comprehensive Cancer Network favorable intermediate-risk prostate cancer is a heterogeneous disease with varied oncologic and survival outcomes. We describe the Michigan Urological Surgery Improvement Collaborative's experience with the use of active surveillance and the short-term oncologic outcomes for men with favorable intermediate-risk prostate cancer.Materials and Methods:We reviewed the Michigan Urological Surgery Improvement Collaborative registry for men diagnosed with favorable intermediate-risk prostate cancer from 2012-2020. The proportion of men with favorable intermediate-risk prostate cancer managed with active surveillance was calculated by year of diagnosis. For men selecting active surveillance, the Kaplan-Meier method was used to estimate treatment-free survival. To assess for the oncologic safety of active surveillance, we compared the proportion of patients with adverse pathology and biochemical recurrence-free survival between men undergoing delayed radical prostatectomy after a period of active surveillance with men undergoing immediate radical prostatectomy. RESULTS: Of the 4,275 men with favorable intermediate-risk prostate cancer, 1,321 (31%) were managed with active surveillance, increasing from 13% in 2012 to 45% in 2020. The 5-year treatment-free probability for men with favorable intermediate-risk prostate cancer on active surveillance was 73% for Gleason Grade Group 1 and 57% for Grade Group 2 disease. More men undergoing a delayed radical prostatectomy had adverse pathology (46%) compared with immediate radical prostatectomy (32%, P < .001), yet short-term biochemical recurrence was similar between groups (log-rank test, P = .131). CONCLUSIONS: The use of active surveillance for men with favorable intermediate-risk prostate cancer has increased markedly. Over half of men with favorable intermediate-risk prostate cancer on active surveillance remained free of treatment 5 years after diagnosis. Most men on active surveillance will not lose their window of cure and have similar short-term oncologic outcomes as men undergoing up-front treatment. Active surveillance is an oncologically safe option for appropriately selected men with favorable intermediate-risk prostate cancer.

Initial Management of Indeterminate Renal Lesions in a Statewide Collaborative: A MUSIC-KIDNEY Analysis.

PURPOSE: Renal masses can be characterized as "indeterminate" due to lack of differentiating imaging characteristics. Optimal management of indeterminate renal lesions remains nebulous and poorly defined. We assess management of indeterminate renal lesions within the MUSIC-KIDNEY (Michigan Urological Surgery Improvement Collaborative-Kidney mass: Identifying and Defining Necessary Evaluation and therapY) collaborative. MATERIALS AND METHODS: Each renal mass is classified as suspicious, benign, or indeterminate based on radiologist and urologist assessment. Objectives were to assess initial management of indeterminate renal lesions and the impact of additional imaging and biopsy on characterization prior to treatment. RESULTS: Of 2,109 patients, 444 (21.1%) had indeterminate renal lesions on their initial imaging, which included CT without contrast (36.2%), CT with contrast (54.1%), and MRI (9.7%). Eighty-nine patients (20.0%) underwent additional imaging within 90 days, 8.3% (37/444) underwent renal mass biopsy, and 3.6% (16/444) had reimaging and renal mass biopsy. Additional imaging reclassified 58.1% (61/105) of indeterminate renal lesions as suspicious and 21.0% (22/105) as benign, with only 20.9% (22/105) remaining indeterminate. Renal mass biopsy yielded a definitive diagnosis for 87%. Treatment was performed for 149 indeterminate renal lesions (33.6%), including 117 without reimaging and 123 without renal mass biopsy. At surgery for indeterminate renal lesions, benign pathology was more common in patients who did not have repeat imaging (9.9%) than in those who did (6.7%); for ≤4 cm indeterminate renal lesions, these rates were 11.8% and 4.3%. CONCLUSIONS: About 33% of patients diagnosed with an indeterminate renal lesion underwent immediate treatment without subsequent imaging or renal mass biopsy, with a 10% rate of nonmalignant pathology. This highlights a quality improvement opportunity for patients with cT1 renal masses: confirmation that the lesion is suspicious for renal cell carcinoma based on high-quality, multiphase, cross-sectional imaging and/or histopathological features prior to surgery, even if obtaining subsequent follow-up imaging and/or renal mass biopsy is necessary. When performed, these steps lead to reclassification in 79% and 87% of indeterminate renal lesions, respectively.

Diabetes, Obesity, and Pathological Upstaging in Renal Cell Carcinoma: Results From a Large Multi-institutional Consortium.

PURPOSE: We sought to determine whether clinical risk factors and morphometric features on preoperative imaging can be utilized to identify those patients with cT1 tumors who are at higher risk of upstaging (pT3a). MATERIALS AND METHODS: We performed a retrospective international case-control study of consecutive patients treated surgically with radical or partial nephrectomy for nonmetastatic renal cell carcinoma (cT1 N0) conducted between January 2010 and December 2018. Multivariable logistic regression models were used to study associations of preoperative risk factors on pT3a pathological upstaging among all patients, as well as subsets with those with preoperative tumors ≤4 cm, renal nephrometry scores, tumors ≤4 cm with nephrometry scores, and clear cell histology. We also examined association with pT3a subsets (renal vein, sinus fat, perinephric fat). RESULTS: Among the 4,092 partial nephrectomy and 2,056 radical nephrectomy patients, pathological upstaging occurred in 4.9% and 23.3%, respectively. Among each group independent factors associated with pT3a upstaging were increasing preoperative tumor size, increasing age, and the presence of diabetes. Specifically, among partial nephrectomy subjects diabetes (OR=1.65; 95% CI 1.17, 2.29), male sex (OR=1.62; 95% CI 1.14, 2.33), and increasing BMI (OR=1.03; 95% CI 1.00, 1.05 per 1 unit BMI) were statistically associated with upstaging. Subset analyses identified hilar tumors as more likely to be upstaged (partial nephrectomy OR=1.91; 95% CI 1.12, 3.16; radical nephrectomy OR=2.16; 95% CI 1.44, 3.25). CONCLUSIONS: Diabetes and higher BMI were associated with pathological upstaging, as were preoperative tumor size, increased age, and male sex. Similarly, hilar tumors were frequently upstaged.

Development and Validation of Models to Predict Pathological Outcomes of Radical Prostatectomy in Regional and National Cohorts.

PURPOSE: Prediction models are recommended by national guidelines to support clinical decision making in prostate cancer. Existing models to predict pathological outcomes of radical prostatectomy (RP)-the Memorial Sloan Kettering (MSK) models, Partin tables, and the Briganti nomogram-have been developed using data from tertiary care centers and may not generalize well to other settings. MATERIALS AND METHODS: Data from a regional cohort (Michigan Urological Surgery Improvement Collaborative [MUSIC]) were used to develop models to predict extraprostatic extension (EPE), seminal vesicle invasion (SVI), lymph node invasion (LNI), and nonorgan-confined disease (NOCD) in patients undergoing RP. The MUSIC models were compared against the MSK models, Partin tables, and Briganti nomogram (for LNI) using data from a national cohort (Surveillance, Epidemiology, and End Results [SEER] registry). RESULTS: We identified 7,491 eligible patients in the SEER registry. The MUSIC model had good discrimination (SEER AUC EPE: 0.77; SVI: 0.80; LNI: 0.83; NOCD: 0.77) and was well calibrated. While the MSK models had similar discrimination to the MUSIC models (SEER AUC EPE: 0.76; SVI: 0.80; LNI: 0.84; NOCD: 0.76), they overestimated the risk of EPE, LNI, and NOCD. The Partin tables had inferior discrimination (SEER AUC EPE: 0.67; SVI: 0.76; LNI: 0.69; NOCD: 0.72) as compared to other models. The Briganti LNI nomogram had an AUC of 0.81 in SEER but overestimated the risk. CONCLUSIONS: New models developed using the MUSIC registry outperformed existing models and should be considered as potential replacements for the prediction of pathological outcomes in prostate cancer.

Rapid and active stabilization of visual cortical firing rates across light-dark transitions.

The dynamics of neuronal firing during natural vision are poorly understood. Surprisingly, mean firing rates of neurons in primary visual cortex (V1) of freely behaving rodents are similar during prolonged periods of light and darkness, but it is unknown whether this reflects a slow adaptation to changes in natural visual input or insensitivity to rapid changes in visual drive. Here, we use chronic electrophysiology in freely behaving rats to follow individual V1 neurons across many dark-light (D-L) and light-dark (L-D) transitions. We show that, even on rapid timescales (1 s to 10 min), neuronal activity was only weakly modulated by transitions that coincided with the expected 12-/12-h L-D cycle. In contrast, a larger subset of V1 neurons consistently responded to unexpected L-D and D-L transitions, and disruption of the regular L-D cycle with 60 h of complete darkness induced a robust increase in V1 firing on reintroduction of visual input. Thus, V1 neurons fire at similar rates in the presence or absence of natural stimuli, and significant changes in activity arise only transiently in response to unexpected changes in the visual environment. Furthermore, although mean rates were similar in light and darkness, pairwise correlations were significantly stronger during natural vision, suggesting that information about natural scenes in V1 may be more strongly reflected in correlations than individual firing rates. Together, our findings show that V1 firing rates are rapidly and actively stabilized during expected changes in visual input and are remarkably stable at both short and long timescales.

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

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 × 1011 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.

A miRNA signature predicts benefit from addition of hypoxia-modifying therapy to radiation treatment in invasive bladder cancer.

BACKGROUND: miRNAs are promising biomarkers in oncology as their small size makes them less susceptible to degradation than mRNA in FFPE tissue. We aimed to derive a hypoxia-associated miRNA signature for bladder cancer. METHODS: Taqman miRNA array cards identified miRNA seed genes induced under hypoxia in bladder cancer cell lines. A signature was derived using feature selection methods in a TCGA BLCA training data set. miRNA expression data were generated for 190 tumours from the BCON Phase 3 trial and used for independent validation. RESULTS: A 14-miRNA hypoxia signature was derived, which was prognostic for poorer overall survival in the TCGA BLCA cohort (n = 403, p = 0.001). Univariable analysis showed that the miRNA signature predicted an overall survival benefit from having carbogen-nicotinamide with radiotherapy (HR = 0.30, 95% CI 0.094-0.95, p = 0.030) and performed similarly to a 24-gene mRNA signature (HR = 0.47, 95% CI 0.24-0.92, p = 0.025). Combining the signatures improved performance (HR = 0.26, 95% CI 0.08-0.82, p = 0.014) with borderline significance for an interaction test (p = 0.065). The interaction test was significant for local relapse-free survival LRFS (p = 0.033). CONCLUSION: A 14-miRNA hypoxia signature can be used with an mRNA hypoxia signature to identify bladder cancer patients benefitting most from having carbogen and nicotinamide with radiotherapy.

Limitations of abdominopelvic CT and multiparametric MR imaging for detection of lymph node metastases prior to radical prostatectomy.

PURPOSE: To investigate the performance of pre-surgery CT and multiparametric MRI (mpMRI) to identify lymph node (LN) metastases in the Michigan Urological Surgery Improvement Collaborative (MUSIC). Abdominopelvic CT and mpMRI are commonly used for intermediate- and high-risk prostate cancer (PCa) staging. METHODS: Retrospective analysis of the MUSIC registry identified patients undergoing robot-assisted radical prostatectomy (RP) between 3/2012 and 7/2018. Patients were classified according to pre-surgery imaging modality. Primary outcomes were operating characteristics of CT and mpMRI for detection of pathologic LN involvement (pN1). RESULTS: A total of 10,250 patients underwent RP and 3924 patients (38.3%) underwent CT and/or mpMRI prior to surgery. Suspicion for LN involvement was identified on 2.3% CT and 1.9% mpMRI. Overall, 391 patients were pN1(3.8%), including 0.1% low-, 2.1% intermediate-, and 10.9% high-risk PCa patients. Of 235 pN1 patients that underwent CT prior, far more had negative (91.1%) than positive (8.9%) findings, yielding sensitivity: 8.9%, specificity: 98.3%, negative predictive value (NPV): 92.1%, and positive predictive value (PPV): 32.3% for CT with regard to LN metastases. Similarly, more patients with pN1 disease had negative mpMRI (81.0%) then suspicious or indeterminate MRI (19.0%), yielding sensitivity: 19.0%, specificity: 97.3%, NPV: 95.9%, and PPV: 26.7%. CONCLUSIONS: Abdominopelvic CT and mpMRI have clear limitations in identifying LN metastases. Additional clinicopathologic features should be considered when making management decisions, as 2.1% and 10.9% with intermediate-and high-risk cancer had metastatic LNs. The majority of pN1 patients had a negative CT or a negative/indeterminate mpMRI prior to RP. Pelvic LN dissection should be performed in RP patients with intermediate- or high-risk PCa, independent of preoperative imaging results.

Comparison of renal functional outcomes of active surveillance and partial nephrectomy in the management of oncocytoma.

PURPOSE: To compare functional outcomes of partial nephrectomy (PN) and active surveillance (AS) in oncocytoma. METHODS: Multicenter retrospective analysis of patients with oncocytoma managed with PN or AS (biopsy-confirmed). Primary outcome development of de novo chronic kidney disease (CKD) (eGFR < 60 mL/min/1.73m2). Cox regression Multivariable analysis (MVA) was carried out for predictors of de novo CKD. Linear regression was carried out for factors associated with increasing deltaGFR. Kaplan-Meier Analysis (KMA) was performed to analyze 5-year CKD-free survival. RESULTS: 295 patients were analyzed (224 PN/71 AS, median follow-up 37.4 months). No differences were noted for clinical tumor size (AS 2.6 vs. PN 2.9 cm, p = 0.108), and baseline eGFR (AS 79.6 vs. PN 77, p = 0.9670). Median change in tumor diameter for AS was 0.42 cm. Compared to PN, AS had deltaGFR (-15.3 vs. -6.4 mL/min/1.73m2, p < 0.001) and de novo CKD (28.2% vs. 12.1%, p = 0.002). AS patients who developed CKD had higher RENAL score (p = 0.005) and lower baseline eGFR (73 vs. 91.2 mL/min/1.73m2, p < 0.001) than AS patients who did not. MVA demonstrated increasing age (OR = 1.03, p = 0.025), tumor size (HR = 1.26, p = 0.032) and AS (HR = 4.91, p < 0.001) to be predictive for de novo CKD. Linear regression demonstrated AS was associated with larger decrease in deltaGFR (B = -0.219, p < 0.001). KMA revealed 5-year CKD survival was higher in PN (87%) vs. AS (62%, p < 0.001). CONCLUSION: AS was associated with greater functional decline than PN in oncocytoma. PN may be considered to optimalize renal functional preservation in select circumstances. Further investigation into mechanisms of functional decline in oncocytoma is requisite.

The value of a comprehensive primary outcome - results of a negative randomized control trial in the non-muscle invasive bladder cancer population.

INTRODUCTION American Urological Association (AUA) guidelines recommend intravesical chemotherapy to be given following transurethral resection of a bladder tumor. Prior studies have shown the benefit of mitomycin as well as gemcitabine. However, no study has compared the two agents. MATERIALS AND METHODS: The study was designed as an open label 1:1:1 randomized controlled trial, comparing intravesical mitomycin, gemcitabine and saline as a single intraoperative instillation immediately following transurethral resection of suspected bladder tumor. Primary endpoint was any grade ≥ 3 events according to NCI CTCAE Version 4.03, this captures any return trip to the operating room for recurrence of cancer or other event (benign bladder/urethra). Secondary endpoints were progression free survival for urothelial cell carcinoma and adverse events. RESULTS: A total of 82 patients were enrolled and randomized, unfortunately the trial was suspended early due to protocol deviations. In an intention to treat analysis, freedom from grade > 3 events at 2 years was 74.8% in the no treatment arm, 51.0% in the mitomycin arm, and 56.0% in the gemcitabine arm (p = 0.81). Freedom from cancer recurrence for all patients was 62.3%. In the no treatment arm, it was 78.8%, and 50.7% and 63.6% in the mitomycin arm and gemcitabine arm respectively. (p = 0.28). In a univariate analysis, the only patient variable significantly associated with the primary outcome was pathologic T stage (p < 0.002). CONCLUSION: This study provides an example of a novel, patient centered primary outcome with the goal of determining which treatment paradigms provide the greatest oncologic and clinic benefit.

Development of a Novel Scoring System Quantifies Opportunities to Reduce Surgery for Benign Renal Neoplasms: A Retrospective Quality Improvement Analysis within the MUSIC-KIDNEY Collaborative.

PURPOSE: Nonmalignant pathology has been reported in 15% to 20% of surgeries for cT1 renal masses. We seek to identify opportunities for improvement in avoiding surgery for nonmalignant pathology. MATERIALS AND METHODS: MUSIC-KIDNEY started collecting data in 2017. All patients with cT1 renal masses who had partial or radical nephrectomy for nonmalignant pathology were identified. Category for improvement (none-0, minor-1, moderate-2 or major-3) was independently assigned to each case by 5 experienced kidney surgeons. Specific strategies to decrease nonmalignant pathology were identified. RESULTS: Of 1,392 patients with cT1 renal masses 653 underwent surgery and 74 had nonmalignant pathology (11%). Of these, 23 (31%) cases were cT1b. Radical nephrectomy was performed in 17 (22.9%) patients for 5 cT1a and 12 cT1b lesions. Only 6 patients had a biopsy prior to surgery (5 oncocytoma, 1 unclassified renal cell carcinoma). Review identified 25 cases with minor (34%), 26 with moderate (35%) and 10 with major (14%) quality improvement opportunities. Overall 17% of cases had no quality improvement opportunities identified (12 partial nephrectomy, 1 radical nephrectomy). CONCLUSIONS: Review of patients with cT1 renal masses who underwent surgery for nonmalignant pathology revealed a significant number of cases in which this outcome may have been avoided. Approximately half of cases had moderate or major quality improvement opportunities, with radical nephrectomy for nonmalignant pathology being the most common reason. Our data indicate a lowest achievable and acceptable rate of nonmalignant pathology to be 1.9% and 5.4%, respectively. Avoiding interventions for nonmalignant pathology, particularly radical nephrectomy, is an important focus of quality improvement efforts. Strategies to decrease unnecessary interventions for nonmalignant pathology include greater use of repeat imaging, renal mass biopsy and surveillance.

Impact of Resection Technique on Perioperative Outcomes and Surgical Margins after Partial Nephrectomy for Localized Renal Masses: A Prospective Multicenter Study.

PURPOSE: The impact of resection technique on partial nephrectomy outcomes is controversial. The aim of this study was to evaluate the pattern of resection techniques during partial nephrectomy and the impact on perioperative outcomes, acute kidney injury, positive surgical margins and the achievement of the Trifecta (negative surgical margins, no perioperative Clavien-Dindo grade 2 or greater surgical complications and no postoperative acute kidney injury). MATERIALS AND METHODS: We prospectively collected data on consecutive patients with cT1-2N0M0 renal masses treated with partial nephrectomy at a total of 16 referral centers from September 2014 to March 2015. After partial nephrectomy the resection technique was classified by the surgeon as enucleation, enucleoresection or resection according to the SIB (Surface-Intermediate-Base) margin scores 0 to 2, 3 or 4 and 5, respectively. Multivariable logistic regression analysis was done to evaluate the potential impact of the resection technique on postoperative surgical complications, positive surgical margins, acute kidney injury and Trifecta achievement. RESULTS: Overall 507 patients were included in analysis. The resection technique was classified as enucleation in 266 patients (52%), enucleoresection in 150 (30%) and resection in 91 (18%). The resection technique (enucleoresection vs enucleation and resection) was the only significant predictor of positive surgical margins. Tumor complexity, surgical approach (open and laparoscopic vs robotic) and resection technique (enucleoresection vs enucleation) were significant predictors of Clavien-Dindo grade 2 or greater surgical complications. The surgical approach (open and laparoscopic vs robotic), the resection technique (enucleoresection vs enucleation) and warm ischemia time were significantly associated with postoperative acute kidney injury and Trifecta achievement. CONCLUSIONS: Resection techniques significantly impact surgical complications, early functional outcomes and positive surgical margins after partial nephrectomy of localized renal masses.

Preoperative tranexamic acid does not reduce transfusion rates in major oncologic surgery: Results of a randomized, double-blind, and placebo-controlled trial.

BACKGROUND AND OBJECTIVES: Allogeneic blood transfusions are associated with worse postoperative outcomes in oncologic surgery. The aim of this study was to introduce a preoperative intervention to reduce transfusion rates in this population. METHODS: Adult patients undergoing major oncologic surgery in five categories with similar transfusion rates were recruited. Enrollees received a single preoperative intravenous dose of placebo or tranexamic acid (1000 mg). The primary outcome measure was perioperative transfusion rate. Secondary outcome measures included: estimated blood loss, thromboembolic events, morbidity, hospital length of stay, and readmission rate. RESULTS: Seventy-six patients were enrolled, 39 in the tranexamic acid group and 37 in the placebo group, respectively. Demographics and surgery type were equivalent between groups. The transfusion rates were 8 out of 39 (20.5%) in the tranexamic acid group and 5 out of 37 (13.5%) in the placebo group, respectively (P = .418). Median estimated blood loss was 400 mL (interquartile range [IQR] = 150-600) in the tranexamic acid group compared with 300 mL (IQR = 150-800) in the placebo group (P = .983). There was one pulmonary embolism in each arm and no deep venous thrombosis (P > .999). CONCLUSION: Preoperative administration of tranexamic acid at a 1000 mg intravenous dose does not decrease transfusion rates or estimated blood loss in patients undergoing major oncologic surgery.

Grade Groups Provide Improved Predictions of Pathological and Early Oncologic Outcomes Compared with Gleason Score Risk Groups.

PURPOSE: The GG (Grade Group) system was introduced in 2013. Data from academic centers suggest that GG better distinguishes between prostate cancer risk groups than the Gleason score (GS) risk groups. We compared the performance of the 2 systems to predict pathological/recurrence outcomes using data from the MUSIC (Michigan Urological Surgery Improvement Collaborative). MATERIALS AND METHODS: Patients who underwent biopsy and radical prostatectomy in the MUSIC from March 2012 to June 2017 were classified according to GG and GS. Outcomes included the presence or absence of extraprostatic extension, seminal vesical invasion, positive lymph nodes, positive surgical margins and time to cancer recurrence (defined as postoperative prostate specific antigen 0.2 ng/ml or greater). Logistic and Cox regression models were used to compare the difference in outcomes. RESULTS: A total of 8,052 patients were identified. When controlling for patient characteristics, significantly higher risks of extraprostatic extension, seminal vesical invasion and positive lymph nodes were observed for biopsy GG 3 vs 2 and for GG 5 vs 4 (p <0.001). Biopsy GGs 3, 4 and 5 also showed shorter time to biochemical recurrence than GGs 2, 3 and 4, respectively (p <0.001). GGs 3, 4 and 5 at radical prostatectomy were each associated with a greater probability of recurrence compared to the next lower GG (p <0.001). GG (vs GS) had better predictive power for extraprostatic extension, seminal vesical invasion, positive lymph nodes and biochemical recurrence. CONCLUSIONS: GG at biopsy and radical prostatectomy allows for better discrimination of recurrence-free survival between individual risk groups than GS risk groups with GGs 2, 3, 4 and 5 each incrementally associated with increased risk.