Mark W. Ball

Five-year Analysis of a Multi-institutional Prospective Clinical Trial of Delayed Intervention and Surveillance for Small Renal Masses: The DISSRM Registry ☆

BACKGROUND A growing body of retrospective literature is emerging regarding active surveillance (AS) for patients with small renal masses (SRMs). There are limited prospective data evaluating the effectiveness of AS compared to primary intervention (PI). OBJECTIVE To determine the characteristics and clinical outcomes of patients who chose AS for management of their SRM. DESIGN, SETTING, AND PARTICIPANTS From 2009 to 2014, the multi-institutional Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry prospectively enrolled 497 patients with solid renal masses ≤4.0cm who chose PI or AS. INTERVENTION AS versus PI. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The registry was designed and powered as a noninferiority study based on historic recurrence rates for PI. Analyses were performed in an intention-to-treat manner. Primary outcomes were overall survival (OS) and cancer-specific survival (CSS). RESULTS AND LIMITATIONS Of the 497 patients enrolled, 274 (55%) chose PI and 223 (45%) chose AS, of whom 21 (9%) crossed over to delayed intervention. AS patients were older, had worse Eastern Cooperative Oncology Group scores, total comorbidities, and cardiovascular comorbidities, had smaller tumors, and more often had multiple and bilateral lesions. OS for PI and AS was 98% and 96% at 2 yr, and 92% and 75% at 5 yr, respectively (log rank, p=0.06). At 5 yr, CSS was 99% and 100% for PI and AS, respectively (p=0.3). AS was not predictive of OS or CSS in regression modeling with relatively short follow-up. CONCLUSIONS In a well-selected cohort with up to 5 yr of prospective follow-up, AS was not inferior to PI. PATIENT SUMMARY The current report is among the first prospective analyses of patients electing for active surveillance of a small renal mass. Discussion of active surveillance should become part of the standard discussion for management of small renal masses.

Trifecta and optimal perioperative outcomes of robotic and laparoscopic partial nephrectomy in surgical treatment of small renal masses: a multi-institutional study

To compare the perioperative outcomes of robotic partial nephrectomy (RPN) with laparoscopic PN (LPN) performed for small renal masses (SRMs), in a large multi‐institutional series and to define a new composite outcome measure, termed ‘optimal outcome’ for the RPN group.

Grade Heterogeneity in Small Renal Masses: Potential Implications for Renal Mass Biopsy

PURPOSE Understanding the degree of phenotypic heterogeneity in a small renal mass may have implications for interpreting renal mass biopsy data. In this study we quantify nuclear grade heterogeneity in small renal masses. MATERIALS AND METHODS Our institutional renal mass database was queried for patients with T1a (less than 4 cm) renal masses stratified by the criteria of imaging diameter less than 2 cm or 2 cm or greater, clear cell or papillary histology, low grade (Fuhrman 1-2) or high grade (Fuhrman 3-4) with tissue available for review. Four consecutive specimens were chosen from each of the 8 strata for a total of 32. All specimens were reanalyzed and the highest Fuhrman grade present in each 10× powered field was recorded. A case was classified as heterogeneous if multiple grades were present and as discordant if the highest Fuhrman grade was present in less than 50% of the specimen. RESULTS A median of 5 slides (IQR 3.5-7.5) and 59, 10× powered fields (IQR 34-109) were examined per patient. Overall 26 samples (81.3%) were heterogeneous, including 15 of 16 (93.8%) high grade specimens. Among all cases 10 (31.3%) were discordant and of high grade specimens 4 (25%) were discordant. Median fraction of low grade tissue in high grade specimens was 38.9% (IQR 12.2-57.2). CONCLUSIONS The majority of small renal masses demonstrated considerable nuclear grade heterogeneity. The greatest degree of heterogeneity and discordance was observed in high grade tumors. One should consider these findings when interpreting renal mass biopsy data as the risk of under sampling high grade tumors may not be insignificant.

Outcomes and predictors of clinical T1 to pathological T3a tumor up-staging after robotic partial nephrectomy: a multi-institutional analysis.

PURPOSE We evaluated the early oncological end point of recurrence-free survival in patients with renal cell carcinoma up-staged from cT1 to pT3a after partial nephrectomy. We also aimed to establish preoperative factors associated with pathological tumor up-staging. MATERIALS AND METHODS A prospective database of robotic partial nephrectomy cases performed at 5 academic centers was queried for patients who underwent surgery for a solitary cT1 renal mass. Patients with pT1-2 renal cell carcinoma were compared to those with pT3a tumors to determine the difference in recurrence-free survival. Preoperative factors associated with cT1 to pT3a up-staging were studied using multivariate logistic regression analysis. RESULTS A total of 1,096 patients underwent robotic partial nephrectomy for a cT1 renal mass. At final pathological evaluation 855 tumors (78.0%) were found to be renal cell carcinoma, of which 41 (4.8%) were up-staged to pT3a. The 24-month recurrence-free survival estimates for pT1-2 and pT3a tumors were 99.2% and 91.8%, respectively (p=0.003). Multivariate analysis revealed that a high vs low R.E.N.A.L. (radius, exophytic/endophytic, nearness to collecting system or sinus, anterior/posterior and location relative to polar lines) nephrometry score was associated with tumor up-staging (OR 2.97, 95% CI 1.20-7.35, p=0.02). On separate multivariate analysis increasing tumor diameter (OR 1.66, 95% CI 1.32-2.08, p<0.001) and hilar location (OR 2.83, 95% CI 1.43-5.61, p=0.003) were also associated with up-staging. CONCLUSIONS At short-term followup patients with renal cell carcinoma up-staged from cT1 to pT3a have reasonable oncological outcomes after partial nephrectomy. Factors associated with tumor up-staging include high tumor complexity, increasing tumor diameter and hilar location. Further studies are needed to determine the comparative efficacy of partial vs radical nephrectomy for small pT3a tumors.

Very-high-risk localized prostate cancer: definition and outcomes

Background:Outcomes in men with National Comprehensive Cancer Network (NCCN) high-risk prostate cancer (PCa) can vary substantially—some will have excellent cancer-specific survival, whereas others will experience early metastasis even after aggressive local treatments. Current nomograms, which yield continuous risk probabilities, do not separate high-risk PCa into distinct sub-strata. Here, we derive a binary definition of very-high-risk (VHR) localized PCa to aid in risk stratification at diagnosis and selection of therapy.Methods:We queried the Johns Hopkins radical prostatectomy database to identify 753 men with NCCN high-risk localized PCa (Gleason sum 8–10, PSA >20 ng ml−1, or clinical stage ⩾T3). Twenty-eight alternate permutations of adverse grade, stage and cancer volume were compared by their hazard ratios for metastasis and cancer-specific mortality. VHR criteria with top-ranking hazard ratios were further evaluated by multivariable analyses and inclusion of a clinically meaningful proportion of the high-risk cohort.Results:The VHR cohort was best defined by primary pattern 5 present on biopsy, or ⩾5 cores with Gleason sum 8–10, or multiple NCCN high-risk features. These criteria encompassed 15.1% of the NCCN high-risk cohort. Compared with other high-risk men, VHR men were at significantly higher risk for metastasis (hazard ratio 2.75) and cancer-specific mortality (hazard ratio 3.44) (P<0.001 for both). Among high-risk men, VHR men also had significantly worse 10-year metastasis-free survival (37% vs 78%) and cancer-specific survival (62% vs 90%).Conclusions:Men who meet VHR criteria form a subgroup within the current NCCN high-risk classification who have particularly poor oncological outcomes. Use of these characteristics to distinguish VHR localized PCa may help in counseling and selection optimal candidates for multimodal treatments or clinical trials.

Increased EZH2 protein expression is associated with invasive urothelial carcinoma of the bladder

OBJECTIVES Elevated polycomb group protein Enhancer of Zest Homolog 2 (EZH2) expression has been associated with progression to more advanced disease in a variety of malignancies. We examined EZH2 protein expression levels in bladder tissue specimens from patients with urothelial carcinoma (UC) and investigated the relationship between EZH2 protein expression and clinical outcomes. MATERIALS AND METHODS Tissue microarrays (TMAs) were constructed using bladder tissue specimens from radical cystectomies performed for UC at our institution between 1994 and 2002. EZH2 expression was measured by immunohistochemistry and scoring was based on percentage and intensity of positive nuclear staining. A receiver operating curve (ROC) was generated to differentiate cancerous from benign lesions using EZH2 protein scores. Recurrence-free survival was estimated using the Kaplan-Meier approach with log-rank test. A multivariate Cox proportional hazards model was used to assess independent contributions. RESULTS A total of 454 TMA specimen spots from 81 patients were evaluated. EZH2 protein levels in invasive high grade UC were significantly elevated compared with adjacent benign urothelium, noninvasive low grade UC, and CIS. EZH2 protein levels were also significantly increased in CIS and noninvasive low grade UC compared with adjacent benign urothelium. We found no association between EZH2 protein expression and clinical outcomes following radical cystectomy in our cohort of patients. CONCLUSION EZH2 overexpression is a common event in UC of the bladder. Elevated EZH2 protein levels are associated with more aggressive bladder cancer, including invasive UC. EZH2 may therefore serve as a useful biomarker for UC.

Prospective Evaluation of 99mTc-sestamibi SPECT/CT for the Diagnosis of Renal Oncocytomas and Hybrid Oncocytic/Chromophobe Tumors

UNLABELLED Nuclear imaging offers a potential noninvasive means of determining the histology of renal tumors. The aim of this study was to evaluate the accuracy of technetium-99m ((99m)Tc)-sestamibi single-photon emission computed tomography/x-ray computed tomography (SPECT/CT) for the differentiation of oncocytomas and hybrid oncocytic/chromophobe tumors (HOCTs) from other renal tumor histologies. In total, 50 patients with a solid clinical T1 renal mass were imaged with (99m)Tc-sestamibi SPECT/CT prior to surgical resection. Preoperative SPECT/CT scans were reviewed by two blinded readers, and their results were compared with centrally reviewed surgical pathology data. Following surgery, 6 (12%) tumors were classified as renal oncocytomas and 2 (4%) as HOCTs. With the exception of 1 (2%) angiomyolipoma, all other tumors were renal cell carcinomas (82%). (99m)Tc-sestamibi SPECT/CT correctly identified 5 of 6 (83.3%) oncocytomas and 2 of 2 (100%) HOCTs, resulting in an overall sensitivity of 87.5% (95% confidence interval [CI], 47.4-99.7%). Only two tumors were falsely positive on SPECT/CT, resulting in a specificity of 95.2% (95% CI, 83.8-99.4%). In summary, (99m)Tc-sestamibi SPECT/CT is a promising imaging test for the noninvasive diagnosis of renal oncocytomas and HOCTs. PATIENT SUMMARY We found that the imaging test (99m)Tc-sestamibi SPECT/CT can be used to accurately diagnose two types of benign kidney tumors. This test may be eventually used to help better evaluate patients diagnosed with a renal tumor.

Preoperative predictors of malignancy and unfavorable pathology for clinical T1a tumors treated with partial nephrectomy: a multi-institutional analysis.

PURPOSE To determine preoperative predictors associated with renal cell carcinoma (RCC) and unfavorable pathology in small renal masses treated with partial nephrectomy (PN). MATERIALS AND METHODS PN records from 5 centers were retrospectively queried for patients with a clinically localized single tumor <4 cm on imaging (clinical T1a). Between 2007 and 2013, 1,009 patients met the inclusion criteria. Unfavorable pathology was defined as any grade III or IV RCC or tumors upstaged to pathologic T3a disease. Logistic regression models were used to determine preoperative characteristics associated with RCC and with unfavorable pathology. RESULTS A total of 771 (76.4%) patients were found to have RCC and 198 (19.6%) had unfavorable pathology. On multivariate, bootstrap-adjusted logistic regression analysis, factors associated with the presence of malignancy were imaging tumor size ≥ 3 cm (odds ratio [OR] = 1.46; P = 0.040), male sex (OR = 1.88; P<0.0001), and nephrometry score ≥ 8 (OR = 1.64; P = 0.005). These same factors were independently associated with risk of unfavorable pathology: size ≥ 3 cm (OR = 1.46; P = 0.021), male sex (OR = 2.35; P<0.0001), and nephrometry score ≥ 8 (OR = 1.49; P = 0.015). The c statistic was 0.62 for the predicting malignancy and 0.63 for unfavorable pathology. CONCLUSIONS In this multi-institutional cohort, male sex, imaging tumor size ≥ 3 cm, and nephrometry score ≥ 8 were predictors of RCC and adverse pathology following PN. These factors may assist in risk stratification and selective renal mass biopsy before decision making. Further studies are necessary to validate these findings.

Fluoroquinolone Resistance in the Rectal Carriage of Men in an Active Surveillance Cohort: Longitudinal Analysis

PURPOSE Rectal swabs can identify men with fluoroquinolone resistant bacteria and decrease the infection rate after transrectal ultrasound guided prostate biopsy by targeted antimicrobial prophylaxis. We evaluated the rate of fluoroquinolone resistance in an active surveillance cohort with attention to factors associated with resistance and changes in resistance with time. MATERIALS AND METHODS We evaluated 416 men with prostate cancer on active surveillance who underwent rectal swabs to assess the rate of fluoroquinolone resistance compared to that in men undergoing diagnostic transrectal ultrasound guided prostate biopsy. The chi-square test and Student t-test were used to compare categorical and continuous variables, respectively. Poisson regression analysis was used for multivariate analysis. RESULTS On the initial swab fluoroquinolone resistance was found in 95 of 416 men (22.8%) on active surveillance compared to 54 of 221 (24.4%) in the diagnostic biopsy cohort (p = 0.675). Diabetes was found in 4.0% of the fluoroquinolone sensitive group vs 14.7% of the resistant group (p <0.001). Biopsy history was not associated with resistance. Of those with a resistant first swab 62.9% had a resistant second swab and 88.9% of those with 2 resistant swabs showed resistance on the third swab. Of men with a sensitive first swab 10.6% showed resistance on the second swab and 10.6% of those with 2 sensitive swabs had resistant third swabs. CONCLUSIONS One of 4 men who present for surveillance and diagnostic transrectal ultrasound guided prostate biopsy have rectal flora resistant to fluoroquinolone. Resistance is significantly associated with diabetes but the number of prior biopsies is not. Men with fluoroquinolone resistant flora tend to remain resistant with time.

Initial Experience Using 99mTc-MIBI SPECT/CT for the Differentiation of Oncocytoma From Renal Cell Carcinoma

Purpose The differentiation of oncocytoma from renal cell carcinoma (RCC) remains a challenge with currently available cross-sectional imaging techniques. As a result, a large number of patients harboring a benign oncocytoma undergo unnecessary surgical resection. In this study, we explored the utility of 99mTc-MIBI SPECT/CT for the differentiation of these tumors based on the hypothesis that the large number of mitochondria in oncocytomas would lead to increased 99mTc-MIBI uptake. Patients and Methods In total, 6 patients (3 with oncocytoma and 3 with RCC) were imaged with 99mTc-MIBI SPECT/CT. Relative quantification was performed by measuring tumor-to-normal renal parenchyma background ratios. Results All 3 oncocytomas demonstrated radiotracer uptake near or above the normal renal parenchymal uptake (range of uptake ratios, 0.85–1.78). In contrast, the 3 RCCs were profoundly photopenic relative to renal background (range of uptake ratios, 0.21–0.31). Conclusions 99mTc-MIBI SPECT/CT appears to be of value in scintigraphically distinguishing benign renal oncocytoma from RCC.