Arthur I. Sagalowsky

Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients

OBJECTIVES To review a large single-center experience of patients treated for upper tract transitional cell carcinoma (TCC) with extended follow-up in order to identify patterns of recurrence, assess patient outcomes, and determine the impact of traditional prognostic factors. METHODS We reviewed 252 patients treated surgically for upper tract TCC with a median follow-up of 64 months. Most patients (77%) underwent nephroureterectomy, whereas 17% were treated with a parenchymal sparing approach. Traditional prognostic factors including age, sex, tumor stage, grade, location, and type of surgical treatment were analyzed with respect to disease recurrence and survival. RESULTS Disease relapse occurred in 67 patients (27%) at a median time of 12.0 months. Recurrences were local in the retroperitoneum (9%), the bladder (51%), remaining upper tract (18%), or distant in the lung, bone, or liver (22%). The 6 patients with local relapse were among the 73 patients with pT3 or pT4 tumors, and all died of TCC at a median time from diagnosis of 37 months. Significant prognostic factors for recurrence by univariate analysis were tumor grade (P = 0.0014) and stage (P = 0.0001). On multivariate analysis, only tumor stage (P = 0.017) and treatment modality (P = 0.020) were predictors of recurrence. Actuarial 5-year disease-specific survival rates by primary tumor stage were 100% for Ta/cis, 91.7% for T1, 72.6% for T2, and 40.5% for T3. Patients with primary Stage T4 tumors had a median survival of 6 months. Although tumor stage and grade correlated with disease-specific survival on univariate analysis, only patient age (P = 0.042) and stage (P = 0.0001) were significant on multivariate analysis with the type of surgical procedure performed approaching significance (P = 0.0504). CONCLUSIONS Primary tumor stage and surgical procedure performed (radical versus parenchymal sparing) are important predictors of disease recurrence. Patient age and tumor stage were the only predictors of disease-specific survival on multivariate analysis with the type of surgical procedure approaching significance. Radical nephroureterectomy achieves excellent local control even in the setting of locally advanced (pT3 or T4) disease. The major clinical feature in this setting is distant failure, and the development of effective systemic therapy is needed to improve the outcome in these patients.

BAP1 loss defines a new class of renal cell carcinoma

The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes, including BAP1. The BAP1 protein, a nuclear deubiquitinase, is inactivated in 15% of clear cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation but not deubiquitination of monoubiquitinated histone 2A lysine 119 (H2AK119ub1). BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Notably, mutations in BAP1 and PBRM1 anticorrelate in tumors (P = 3 × 10−5), and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q = 0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q = 0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.

Nomograms provide improved accuracy for predicting survival after radical cystectomy

Aims: To develop multivariate nomograms that determine the probabilities of all-cause and bladder cancer–specific survival after radical cystectomy and to compare their predictive accuracy to that of American Joint Committee on Cancer (AJCC) staging. Methods: We used Cox proportional hazards regression analyses to model variables of 731 consecutive patients treated with radical cystectomy and bilateral pelvic lymphadenectomy for bladder transitional cell carcinoma. Variables included age of patient, gender, pathologic stage (pT), pathologic grade, carcinoma in situ, lymphovascular invasion (LVI), lymph node status (pN), neoadjuvant chemotherapy (NACH), adjuvant chemotherapy (ACH), and adjuvant external beam radiotherapy (AXRT). Two hundred bootstrap resamples were used to reduce overfit bias and for internal validation. Results: During a mean follow-up of 36.4 months, 290 of 731 (39.7%) patients died; 196 of 290 patients (67.6%) died of bladder cancer. Actuarial all-cause survival estimates were 56.3% [95% confidence interval (95% CI), 51.8-60.6%] and 42.9% (95% CI, 37.3-48.4%) at 5 and 8 years after cystectomy, respectively. Actuarial cancer-specific survival estimates were 67.3% (62.9-71.3%) and 58.7% (52.7-64.2%) at 5 and 8 years, respectively. The accuracy of a nomogram for prediction of all-cause survival (0.732) that included patient age, pT, pN, LVI, NACH, ACH, and AXRT was significantly superior (P = 0.001) to that of AJCC staging–based risk grouping (0.615). Similarly, the accuracy of a nomogram for prediction of cancer-specific survival that included pT, pN, LVI, NACH, and AXRT (0.791) was significantly superior (P = 0.001) to that of AJCC staging–based risk grouping (0.663). Conclusions: Multivariate nomograms provide a more accurate and relevant individualized prediction of survival after cystectomy compared with conventional prediction models, thereby allowing for improved patient counseling and treatment selection.

Use of combined apoptosis biomarkers for prediction of bladder cancer recurrence and mortality after radical cystectomy

BACKGROUND Deregulation of apoptosis is a characteristic of human carcinogenesis. We aimed to investigate expression of the apoptosis markers Bcl-2, caspase-3, P53, and survivin and the association with oncological outcomes of patients treated by radical cystectomy and bilateral lymphadenectomy for urothelial-cell carcinoma of the bladder. METHODS Bcl-2, caspase-3, P53, and survivin immunostaining was undertaken on serial tissue microarrays containing cores from 226 consecutive patients (median follow-up 36.9 months [IQR 13.3-79.0]). 200 bootstrap resamples with replacement were done to reduce overfit bias and for internal validation. FINDINGS Expression of Bcl-2, caspase-3, P53, and survivin was altered in 73 (32%), 111 (49%), 120 (53%), and 141 (64%) patients, respectively. By univariate analysis, altered expression of Bcl-2, caspase-3, P53, and survivin were all associated with high probability of disease recurrence (hazard ratio 2.24 [95% CI 1.51-3.32], p<0.001; 1.73 [1.16-2.59], p=0.007; 2.70 [1.77-4.12], p<0.001; and 2.32 [1.48-3.63], p<0.001) and disease-specific mortality (2.06 [1.33-3.18], p=0.001; 2.35 [1.48-3.73], p<0.001; 3.23 [1.98-5.28], p<0.001; and 2.64 [1.57-4.44], p<0.001; respectively). Risk of recurrence and disease-specific mortality progressively grew with increasing number of altered biomarkers. By multivariate analysis, alteration of four markers was independently associated with high rates of disease recurrence (4.03 [1.23-13.16], p=0.021) and disease-specific mortality (6.84 [1.43-32.63], p=0.016). Addition of the number of altered markers to a model that included standard predictors significantly enhanced its predictive accuracy for disease recurrence and disease-specific survival. INTERPRETATION Bcl-2, caspase-3, P53, and survivin have a cooperative effect on progression of bladder cancer. Assessment of combined apoptosis marker status and number of altered markers in patients treated by radical cystectomy provides prognostic information that could help to identify those at high risk for disease recurrence and mortality, who could benefit from early adjuvant treatment.

Multiple biomarkers improve prediction of bladder cancer recurrence and mortality in patients undergoing cystectomy

Tested was whether the assessment of 5 established bladder cancer biomarkers (p53, pRB, p21, p27, and cyclin E1) could improve the ability to predict disease recurrence and cancer‐specific survival after radical cystectomy in patients with pTa‐3N0M0 urothelial carcinoma of the bladder (UCB).

Multicenter Phase 2 Trial of Sirolimus for Tuberous Sclerosis: Kidney Angiomyolipomas and Other Tumors Regress and VEGF- D Levels Decrease

Background Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2. Methods We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas. Results 36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1–2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline). Conclusions Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC. Trial Registration Clinicaltrials.gov NCT00126672

Histopathology of surgically managed renal tumors: analysis of a contemporary series

OBJECTIVES To review the pathologic findings of a contemporary series of surgically treated renal tumors suspicious for malignancy to assess the frequency of benign disease in the modern era. The extensive application of modern imaging techniques has led to an increase in the number of incidentally discovered solid renal masses, many of which are small. A significant proportion of small renal tumors are benign or are low-grade malignancies. METHODS The records of all patients at our institution who underwent treatment for a renal mass suspicious for malignancy between November 1999 and July 2002 were retrospectively reviewed. RESULTS A total of 173 patients with 186 renal tumors had pathologic information available for analysis. Of the 186 tumors, 48% were discovered incidentally. For masses 4 cm or less, the percentage of incidentally discovered tumors increased to 58%. The pathologic evaluation demonstrated malignancy in 160 (86%) and benignity in 26 (14%) overall. For tumors 4 cm or less, 18 (20%) of 90 were benign; for tumors between 4 and 7 cm, 8 (17%) of 47 benign. No tumors greater than 7 cm were benign. All renal cell carcinomas less than 2 cm in size were Fuhrman grade 1 or 2. CONCLUSIONS Small renal tumors, many of which are incidentally discovered, are often benign or are low-grade malignancies. For tumors 4 cm or less, the frequency of benign pathologic findings is greater than previously quoted in published reports. As a result, we recommend parenchymal-sparing approaches whenever possible.

Soft Tissue Surgical Margin Status is a Powerful Predictor of Outcomes After Radical Cystectomy: A Multicenter Study of More Than 4,400 Patients

PURPOSE We evaluated the association of soft tissue surgical margins with characteristics and outcomes of patients treated with radical cystectomy for urothelial carcinoma of the bladder. MATERIALS AND METHODS We retrospectively collected the data of 4,410 patients treated with radical cystectomy and pelvic lymphadenectomy without neoadjuvant chemotherapy at 12 academic centers in the United States, Canada and Europe. A positive soft tissue surgical margin was defined as presence of tumor at inked areas of soft tissue on the radical cystectomy specimen. RESULTS Positive soft tissue surgical margins were identified in 278 patients (6.3%). On univariate analysis positive soft tissue surgical margin was significantly associated with advanced pT stage, higher tumor grade, lymphovascular invasion and lymph node metastasis (p <0.001). Actuarial 5-year recurrence-free and cancer specific survival probabilities were 62.8% +/- 0.8% and 69% +/- 0.8% for patients without soft tissue surgical margins vs 21.6% +/- 3.1% and 26.4% +/- 3.3% for those with positive soft tissue surgical margins (p <0.001). On multivariable analyses adjusting for the effect of standard clinicopathological features and adjuvant chemotherapy positive soft tissue surgical margin was an independent predictor of disease recurrence and cancer specific mortality (HR 1.52 and HR 1.51, p <0.001, respectively). Soft tissue surgical margin retained independent predictive value in subgroups with advanced disease such as pT3Nany, pT4Nany or Npositive. CONCLUSIONS Positive soft tissue surgical margin is a strong predictor of recurrence and eventual death from urothelial carcinoma of the bladder. Soft tissue surgical margin status should always be reported in the pathological reports after radical cystectomy. Due to uniformly poor outcomes patients with positive soft tissue surgical margins should be considered for studies on adjuvant local and/or systemic therapy.

Intermediate comparison of partial nephrectomy and radiofrequency ablation for clinical T1a renal tumours

To compare the intermediate‐term outcomes of patients with clinical T1a renal tumours who were treated with nephron‐sparing surgery by partial nephrectomy (PN), the preferred approach for small (cT1a) renal tumours, or radiofrequency ablation (RFA), recently offered to selected patients as an alternative, less morbid technique.

Combination of Multiple Molecular Markers Can Improve Prognostication in Patients With Locally Advanced and Lymph Node Positive Bladder Cancer

PURPOSE We tested whether the combination of 4 established cell cycle regulators (p53, pRB, p21 and p27) could improve the ability to predict clinical outcomes in a large multi-institutional collaboration of patients with pT3-4N0 or pTany Npositive urothelial carcinoma of the bladder. We also assessed whether the combination of molecular markers is superior to any individual biomarker. MATERIALS AND METHODS The study comprised 692 patients with pT3-4N0 or pTany Npositive urothelial carcinoma of the bladder treated with radical cystectomy and bilateral lymphadenectomy (median followup 5.3 years). Scoring was performed using advanced cell imaging and color detection software. The base model incorporated patient age, gender, stage, grade, lymphovascular invasion, number of lymph nodes removed, number of positive lymph nodes, concomitant carcinoma in situ and adjuvant chemotherapy. RESULTS Individual molecular markers did not improve the predictive accuracy for disease recurrence and cancer specific mortality. Combination of all 4 molecular markers into number of altered molecular markers resulted in significantly higher predictive accuracy than any single biomarker (p <0.001). Moreover addition of number of altered molecular markers to the base model significantly improved the predictive accuracy for disease recurrence (3.9%, p <0.001) and cancer specific mortality (4.3%, p <0.001). Addition of number of altered molecular markers retained statistical significance for improving the prediction of clinical outcomes in the subgroup of patients with pT3N0 (280), pT4N0 (83) and pTany Npositive (329) disease (p <0.001). CONCLUSIONS While the status of individual molecular markers does not add sufficient value to outcome prediction in patients with advanced urothelial carcinoma of the bladder, combinations of molecular markers may improve molecular staging, prognostication and possibly prediction of response to therapy.