Faculty Bibliography

INTRODUCTION/BACKGROUND:Many patients with small renal masses (SRM) undergo surgical resection of benign and potentially indolent renal masses. We review the available literature to quantify the proportion of renal tumors that are low-risk based on clinical radiographic size, and quantify the number of low-risk masses surgically removed in the United States. METHODS:We systematically reviewed the literature for studies including pathologic findings after excision of renal masses. Inclusion criteria required studies capture both benign and malignant histology at surgical pathology, tumor grade, and stratification by radiographic tumor size. We queried our institutional database using the same parameters. Meta-analysis results were applied to SEER incidence and management data for renal masses. Very-low-risk tumors were defined as benign or grade 1 cT1a, and low-risk tumors as benign, grade 1, or grade 2 cT1a. RESULTS:A total of 733 titles were reviewed at title screening with 6 full text articles and our institutional database included for meta-analysis. Pooled estimates of benign, very-low-risk, and low-risk tumors were stratified by tumor size: ≤2 cm (25.5%, 40.1%, and 89.3%), 2 to 3 cm (21.2%, 34.1%, and 84.5%), 3 to 4 cm (16.1%, 26.6%, and 77.1%), 4 to 6 cm (11.9%, 23.8%, and 66.4%), and >6 cm (7.2%, 12.6%, and 50.3%). An estimated 3,300 benign, 5,400 very-low-risk, and 13,600 low-risk SRMs were resected in 2014 in the United States. CONCLUSION/CONCLUSIONS:A substantial portion of patients with SRM are undergoing surgical excision despite harboring tumors of low metastatic potential. The rate of high-grade histology increased with increasing clinical radiographic size, which can be used in counseling and decision-making regarding placement on active surveillance. The number of low-risk SRM removed annually in the United States increased from 8,500 in 2000 to 13,600 in 2014 with stabilization in recent years.

BACKGROUND:The rising incidence of renal cell carcinoma (RCC) since the 1980s has been accompanied by stage migration toward early-stage (stage I) cancers. Stage migration drove an apparent increase in survival for RCC since the 1980s, but it is unclear whether it remains a contributor more recently. OBJECTIVE:To determine whether clinical stage migration has persisted and the relative impact of stage migration versus improvements in treatment on survival for RCC. DESIGN, SETTING, AND PARTICIPANTS/METHODS:An epidemiologic assessment of stage migration and survival for 262 597 patients at diagnosis of RCC (2004-2015) across >1500 facilities in the National Cancer Database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS/UNASSIGNED:Proportion of patients over time was assessed by clinical stage at diagnosis via Cochran-Armitage chi-square tests and linear regression. Mortality data were assessed with the Kaplan-Meier method for 5-yr overall survival, Cox proportional hazards regression, and propensity score matching to differentiate the impact of treatment including systemic therapy from stage migration. RESULTS AND LIMITATIONS/CONCLUSIONS:Greater diagnosis of clinical stage I disease (70%; p<0.001) was observed, with decreased diagnosis of stage III (8%; p<0.001) and stage IV (11%; p<0.001) up to 2007 followed by stabilization through 2015. Tumor size continues to decrease for localized tumors (mean-0.22cm stage I and-1.24cm stage II, 2004-2015). Histology demonstrated significant associations with stage. Five-year overall survival improved (67.9% [2004] to 72.3% [2010]) with gains in advanced RCC but not localized tumors. Models confirmed improved survival in recent years for stage IV patients. Systemic therapy was associated with improved survival (hazard ratio 0.811 [0.786-0.837], p<0.001). National Cancer Database limitations apply. CONCLUSIONS:The proportion of patients presenting with stage I RCC has stabilized (70%), suggesting that stage migration may have ended. Localized tumors are detected with decreasing size, while advanced cancers have remained stable. Only 11% of patients now present with distant metastatic disease, but 5-yr overall survival is improving in recent years due to improved treatments rather than stage migration. PATIENT SUMMARY/UNASSIGNED:In this study, we found that stage migration toward early-stage cancers has ended for renal cell carcinoma (RCC). However, improved treatment for advanced RCC appears to be responsible for improved survival in recent years.

OBJECTIVES/OBJECTIVE:To perform a comparative analysis of three current management strategies for patients with lymph node metastases (LNM; pN1) following radical prostatectomy (RP): observation, androgen-deprivation therapy (ADT), and external beam radiation therapy (EBRT) + ADT. PATIENTS AND METHODS/METHODS:Patients with LNM after RP were identified using the National Cancer Database (2004-2013). Exclusion criteria included any use of radiation therapy or ADT before RP, clinical M1 disease, or incomplete follow-up data. Patients were categorised according to postoperative management strategy. The primary outcome was overall survival (OS). Kaplan-Meier curves and adjusted multivariable Cox proportional hazards models were employed. Sub-analyses further evaluated patient risk stratification and time to receipt of adjuvant therapy. RESULTS:A total of 8 074 patients met the inclusion criteria. Postoperatively, 4 489 (55.6%) received observation, 2 065 (25.6%) ADT, and 1 520 (18.8%) ADT + EBRT. The mean (median; interquartile range) follow-up was 52.3 (48.0; 28.5-73.5) months. Patients receiving ADT or ADT + EBRT had higher pathological Gleason scores, T-stage, positive surgical margin rates, and nodal burden. Adjusted multivariable Cox models showed improved OS for ADT + EBRT vs observation (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.64-0.94; P = 0.008) and vs ADT (HR 0.76, 95% CI: 0.63-0.93; P = 0.007). There was no difference in OS for ADT vs observation (HR 1.01, 95% CI: 0.87-1.18; P = 0.88). Findings were similar when restricting adjuvant cohorts for timing of adjuvant therapy. There was no difference in OS between groups for up to 2 549 (31.6%) patients lacking any of the following adverse features: ≥pT3b disease, Gleason score ≥9, three or more positive nodes, or positive surgical margin. CONCLUSIONS:For patients with LNM after RP, the use of adjuvant ADT + EBRT improved OS in the majority of patients, especially those with adverse pathological features. Conversely, adjuvant therapy did not confer significant OS benefit in up to 30% of patients without high-risk features, who may be managed with observation and forego the morbidity associated with immediate ADT or radiation.

INTRODUCTION:A number of patients who elect active surveillance of their small renal masses (≤4 cm) subsequently pursue delayed intervention (DI). The indications, timing, and rates of DI have not been well determined prospectively. MATERIALS AND METHODS:Data from Delayed Intervention and Surveillance for Small Renal Masses, a prospective, multi-institutional registry was utilized to evaluate factors associated with DI between 2009 and 2018. RESULTS:Of 371 patients enrolled in AS, 46 (12.4%) pursued DI. Patients who pursued DI spent a median 12 months on surveillance (interquartile range 5.5-23.6), had better functional status (P < 0.01), and had greater median growth rate vs. those who remained on surveillance (0.38 vs. 0.05, P < 0.001). Indications for intervention included growth rate >0.5 cm/y for 23 (50%) patients, patient preference for 22 (47.8%) patients, and qualification for renal transplant in 1 (2.2%) patient. Thirty-two patients (69.6%) underwent nephron-sparing surgery, 5 (10.9%) underwent radical nephrectomy, and 9 (19.6%) underwent percutaneous cryoablation. Renal mass biopsy was utilized in 37 (11.4%) and 15 (32.7%) patients in the AS and DI arms, respectively (P = 0.04). No patients experienced metastatic progression or died of kidney cancer. CONCLUSIONS:As nearly 50% of patients pursue DI secondary to anxiety in the absence of clinical progression, comprehensive counseling is essential to determine if patients are suitable for a surveillance protocol. AS remains a safe initial management option for many patients but may not be a durable strategy for patients who are acceptable surgical candidates with an extended life expectancy. DI does not compromise oncologic outcomes or limit treatment options.

PURPOSE:Intermediate risk prostate cancer is a heterogenous classification with favorable proposed criteria based on men treated with radiation therapy. However, there is uncertain application to active surveillance. We quantified the rate of adverse surgical pathology and implications for survival in patients at favorable intermediate risk compared to those with low risk prostate cancer. MATERIALS AND METHODS:We performed a comparative cohort study of men with prostate cancer from 2009 to 2013 in the National Cancer Database who underwent radical prostatectomy. The study primary end point was adverse pathology, defined as Grade Group 3 or greater/pT3b/pN1. Various favorable intermediate risk definitions were evaluated, including the Memorial Sloan Kettering Cancer Center definition of Grade Group 2 or less with only 1 intermediate risk factor (Grade Group 2/cT2b/prostate specific antigen 10 to 20 ng/ml), which we defined as type 1 intermediate risk. The remaining patients at intermediate risk were classified as type 2 intermediate risk. Log binomial, logistic and Cox proportional hazards regression models were applied. RESULTS:Adverse pathological findings were noted in 3,519 of the 51,688 patients (6.8%) at low risk and 8,888 of the 42,720 Grade Group 2 patients (20.8%) at intermediate risk (RR 3.06, 95% CI 2.95-3.17, p <0.001). Stratification by prostate specific antigen and volume minimally impacted the absolute rate. Results were similar for the Memorial Sloan Kettering Cancer Center definition (type 1 intermediate risk). Type 2 intermediate risk led to a greater risk of adverse pathology (RR 8.52, 8.23-8.82, p <0.001) and Grade Group 1 intermediate risk led to lower risk (RR 2.00, 1.86-2.16, p <0.001). Patients at favorable intermediate risk had worse overall survival than patients at low risk in adjusted models due to adverse pathology. CONCLUSIONS:Adverse pathology at radical prostatectomy was observed at a threefold higher rate in patients classified at favorable intermediate risk compared to low risk, leading to worse overall survival. Men at intermediate risk may be better classified as types 1 and 2 since none showed pathological outcomes similar to those of men at low risk.

PURPOSE:High risk upper tract urothelial carcinoma has been associated with poor survival outcomes. Limited retrospective data support neoadjuvant chemotherapy prior to radical nephroureterectomy. To validate prior findings we evaluated differences in the pathological stage distribution in patients with high risk upper tract urothelial carcinoma based on the administration of neoadjuvant chemotherapy before radical nephroureterectomy. MATERIALS AND METHODS:We retrospectively analyzed the records of 240 patients with upper tract urothelial carcinoma at The Johns Hopkins Hospital from 2003 to 2017. Patients with biopsy proven high grade disease and a visible lesion on cross-sectional imaging were offered neoadjuvant chemotherapy prior to radical nephroureterectomy. A control group of a time matched cohort of patients with biopsy proven high grade disease underwent extirpative surgery alone. The chi-square and Fisher exact tests were used to evaluate clinical and pathological variables between the cohorts. RESULTS:There were 32 patients in the study group and 208 in the control group. Significantly lower pathological stage was noted in the study group than in the control group (p <0.001). Significantly fewer patients with pT2 disease or higher were treated with neoadjuvant chemotherapy (37.5% vs 59.6%, p = 0.02). There was a 46.5% reduction in the prevalence of pT3 disease or higher in study group patients without clinically node positive or low volume metastatic disease (25.9% vs 48.4%, p = 0.04). A 9.4% complete remission rate was observed in patients who underwent neoadjuvant chemotherapy. CONCLUSIONS:Patients with high risk upper tract urothelial carcinoma treated with neoadjuvant chemotherapy were noted to have a lower pathological stage distribution than patients treated with radical nephroureterectomy alone.

Atypical hemolytic uremic syndrome (aHUS) is a rare life-threatening thrombotic microangiopathy (TMA) affecting multiple organ systems. Recently, aHUS has been shown to be associated with uncontrolled complement activation due to mutations in the alternative pathway of complement components paving the way for targeted drug therapy. By meta-analysis of case reports, we discuss the impact of new treatment strategies on the resolution time of aHUS symptoms and mortality, and the distribution of genetic mutations. A PubMed/Medline search was conducted for "atypical hemolytic uremic syndrome" case reports published between November 2005 and November 2015. R Version 3.2.2 was used to calculate descriptive statistics and perform univariate analyses. Wilcoxon rank-sum test was used to compare time to symptoms resolution, creatinine and platelet count normalization across the treatment and mutation carrier groups. A total of 259 aHUS patients were reported in 176 articles between 2005 and 2015. In the last 5-year period compared to the precedent, there was an increase in the number of aHUS cases reported (180 vs. 79 cases) and the use of eculizumab also increased (6.3% to 46.1%, P < 0.000), although plasma exchange usage did not change (P = 0.281). CFH antibodies were present in a significantly higher number of patients treated with plasma exchange therapy (19.1%, P = 0.000) while none of the non-plasma exchange therapy group had CFH antibodies. Most common mutation was CFH (50%, 69/139) followed by CFHR1 (35%, 30/85), MCP (22.8%, 23/101) and CFI (16.6%, 17/102). Time to symptoms resolution and serum creatinine or platelet count normalization were not significantly different between eculizumab and non-eculizumab group (P = 0.166, P = 0.361, P = 0.834), and between plasma exchange and non-plasma exchange group (P = 0.150, P = 0.135, P = 0.784). However, both eculizumab and plasma exchange groups had early platelet recovery (22 vs. 30 days and 25.5 vs. 32.5 days), faster creatinine normalization (27 vs. 30.5 days and 27 vs. 37 days) and interestingly, a longer period for symptoms resolution (45.5 vs. 21 days and 30 vs. 18.5 days) compared to non-eculizumab and non-plasma exchange groups. Mortality rate decreased with the use of eculizumab significantly (P = 0.045) compared to non-eculizumab group and there was no change in mortality rate with the use of plasma exchange therapy (P = 0.760) compared to non-plasma exchange group. Plasma exchange continues to be the initial treatment of choice for aHUS. Although significant reduction in the mortality rate was noted with the use of eculizumab, there were no differences in time to resolution of symptoms or serum creatinine or platelet normalization with the use of either eculizumab or plasma therapy. Atypical HUS is acute and life-threatening, so plasma exchange may be initiated before the confirmed diagnosis and in patients positive for CFH antibodies. Eculizumab therapy should be considered once aHUS is confirmed by genetic testing.