Karnofsky performance status predicts overall survival, cancer-specific survival, and progression-free survival following radical cystectomy for urothelial carcinoma.

OBJECTIVE: Radical cystectomy (RC) can provide a survival advantage in patients with urothelial carcinoma of the bladder, but not without significant morbidity rates. Whether the ability of preoperative comorbidity or performance status metrics can stratify patients to overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) following RC is unclear. We analyze our RC experience from 2005 to 2010 to assess the prognostic power of American Society of Anesthesiologists (ASA) score, Charlson Comorbidity Index (CCI), and Karnofsky Performance Status (KPS) index as they relate to OS, CSS, and PFS. MATERIALS AND METHODS: A retrospective analysis was performed of 234 patients who underwent RC between January 2005 and December 2010; of these, 148 patients had sufficient data for OS, CSS, and PFS analysis. Multivariate Cox proportional hazard modeling generated hazard ratios using as independent variables patient age at surgery, gender, ethnicity, preoperative KPS, CCI, and ASA values, pathologic T-staging, the presence of nodal disease, use of radiation therapy, neoadjuvant chemotherapy, and adjuvant chemotherapy. A recursive partition analysis tree divided the population into high- and low-performance groups, and 5-year survival outcomes were evaluated. OS, CSS, and PFS were employed as Kaplan-Meier dependent variables with similar populations comprising high- and low-performance subgroups. RESULTS: Mean CSS was 46.8 months (95 % CI 43.2-50.4) with a 5-year CSS of 75 % and OS of 69 %. Patient age, pathologic T-stage, and KPS were identified as independent predictors of OS and CSS. Analysis of PFS as the continuous dependent variable identified only KPS as a statistically significant predictor of freedom from radiologic progression. No statistically significant predictive value was identified for nodal disease, neoadjuvant chemotherapy, adjuvant chemotherapy, gender, ethnicity, CCI, or ASA in terms of OS, CCS, or PFS. Patients with a KPS ≤ 80 had a shorter survival than patients with a KPS ≥ 90 in terms of OS, CSS, and PFS (log-rank Mantel-Cox: p < 0.01). For patients with a KPS ≤ 80, ~5-year CSS was 42 %, while for patients with a KPS ≥ 90 the 5-year survival was 81 %. These survival curves can be further stratified based on T-stage where patients with a KPS ≥ 90 and T2 have a 5-year CSS of 80 %, whereas patients with a KPS ≤ 80 and >T2 have a ~5-year CSS of 43 % (p < 0.0001). CONCLUSIONS: Our study suggests the use of KPS to have predictive capacity in terms of OS, CSS, and PFS. This information can be used to inform patients' survival expectations prior to proceeding with radical cystectomy.

PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, demonstrates inhibition of proliferation in renal cell carcinoma at nanomolar concentrations and molecular markers predict for sensitivity.

BACKGROUND: PD-0332991 is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6, and was evaluated to determine its anti-proliferative effects in 25 renal cell carcinoma (RCC) cell lines. MATERIALS AND METHODS: Half-maximal inhibitory concentrations (IC50) of PD-0332991 were determined with cell line proliferation assays, as were its effects on the cell cycle, apoptosis, and retinoblastoma (RB) phosphorylation. Molecular markers for response prediction, including p16, p15, cyclin D1 (CCND1), cyclin E1 (CCNE1), E2F transcription factor 1 (E2F1), RB, CDK4 and CDK6, were studied using array comparative genomic hybridization (CGH) and gene expression. RESULTS: IC50 values for PD-0332991 ranged from 25.0 nM to 700 nM, and the agent demonstrated G0/G1 cell-cycle arrest, induction of late apoptosis, and blockade of RB phosphorylation. Through genotype and expression data p16, p15 and E2F1 were identified as having significant association between loss and sensitivity to PD-0332991: p16 (p=0.021), p15 (p=0.047), and E2F1 (p=0.041). CONCLUSION: PD-0332991 has antiproliferative activity in RCC cell lines, and molecular markers predict for sensitivity to this agent.

Gain of chromosome 8q is associated with metastases and poor survival of patients with clear cell renal cell carcinoma.

BACKGROUND: The aim of this study was to evaluate the prevalence of chromosome 8q gain in clear cell renal cell carcinoma (CCRCC) and to correlate the findings with tumor phenotype and disease-specific survival (DSS). METHODS: The tumor karyotypes of 336 consecutive patients with CCRCC were prospectively evaluated with classical cytogenetic analysis. Chromosome 8q status was correlated with clinicopathological variables, and its impact on DSS was evaluated. RESULTS: Gain of 8q occurred in 28 tumors (8.3%). Gain of 8q was associated with a higher risk of regional lymph node (21.4% vs 6.2%, P = .011) and distant metastases (50.0% vs 24.4%, P = .006), and greater tumor sizes (P = .030). Patients with gain of 8q had a 3.22-fold increased risk of death from CCRCC (P < .001). In multivariable analysis, gain of 8q was identified as an independent prognostic factor (hazard ratio, 2.37; P = .006). The concordance index of a multivariable base model increased significantly following inclusion of 8q gain (P = .0015). CONCLUSIONS: Gain of chromosome 8q occurs in a subset of CCRCCs and is associated with an increased risk of metastases and death from CCRCC. Because the proto-oncogene c-MYC is among the list of candidate genes located on 8q, our data suggest that these tumors may have unique pathways activated, which are associated with an aggressive tumor phenotype. If confirmed, defining tumors with gain of 8q may assist in identifying patients who would benefit for specific c-MYC inhibitors or agents that target the MAPK/ERK (mitogen-activated protein kinase) pathway.

Systemic therapy for metastatic renal cell carcinoma: a review and update.

An in-depth understanding of metastatic renal cell carcinoma (mRCC) is important so that practitioners can make informed evidenced-based decisions with patients to optimize not only quantity of life but quality of life as well. Therefore, this review focuses on the biology of mRCC as it relates to targets for therapy, as well as on the small molecules rationally designed with these targets in mind. In addition, anticipated emerging therapies are highlighted, including the new tyrosine kinase inhibitors axitinib and tivozanib, as well as new immune-based therapies such as dendritic cell-based vaccines and antibodies. We also briefly review recent reports from the emerging field of predicting drug response based on molecular markers. And finally, management of metastatic non-clear cell RCC histologies are discussed focusing on available evidence to direct decision making when assessing therapeutic options.

Renal functional outcomes after cryoablation of small renal masses.

BACKGROUND AND PURPOSE: Renal function outcomes after renal cryosurgery have not been widely scrutinized. We report 2-year renal function outcomes from a single-center cohort of patients who were treated with cryoablation for small renal masses. METHODS: We performed a retrospective review of our laparoscopic and percutaneous renal cryoablation experience between January 2003 and April 2007. Global renal function was assessed using measured serum creatinine and estimated glomerular filtration rate (eGFR) (MDRD equation). Chronic kidney disease (CKD) was defined as a serum creatinine level >2.0 mg/dL or eGFR <60 mL/min/1.73 m(2). RESULTS: Sixty-two patients were included in the analysis. Mean follow-up was 30 months (range 13-63 mos). Mean tumor size was 2.33 cm (range 1-4.6 cm). Comorbid conditions were prevalent: 77% hypertension, 35% hyperlipidemia, 31% diabetes mellitus, 39% tobacco use, and 32% heart disease (coronary artery disease/congestive heart failure). Based on eGFR calculations, preoperative CKD was noted in 17 of 62 (27%) patients. De novo CKD was noted in 5 of 45 (11%) patients. Patients in whom de novo CKD developed had lower pretreatment eGFR (71.0 vs 98.4 60 mL/min/1.73 m(2), P = 0.03) and larger tumor size (2.94 vs 2.19 cm, P = 0.04) compared with patients who were maintaining normal renal function. When CKD was defined as creatinine level >2.0 mg/dL, only one and six patients were identified with preoperative and de novo CKD, respectively. CONCLUSIONS: In a cohort of renal cryosurgery patients who were characterized by highly prevalent medical comorbidities, renal function was generally well maintained, with a low rate of de novo CKD based on eGFR calculations. A serum creatinine level >2.0 mg/dL was a less sensitive measure of CKD.

Single center experience with percutaneous and laparoscopic cryoablation of small renal masses.

BACKGROUND AND PURPOSE: While partial nephrectomy remains the gold standard for the management of most small renal masses, increasing experience with renal cryoablation has suggested a viable alternative with a favorable morbidity profile and good efficacy. We report intermediate-term oncologic outcomes from a single-center experience with laparoscopic and percutaneous renal cryoablation. PATIENTS AND METHODS: We performed a retrospective review of our laparoscopic renal cryoablation (LRC) and percutaneous renal cryoablation (PRC) experience between January 2003 and April 2007. Patients with at least 12 months of follow-up were included in the analysis. Follow-up consisted of imaging and laboratory studies at regular intervals. Persistent mass enhancement or interval tumor growth was considered a treatment failure. RESULTS: Sixty-six patients (44% women/56% men; 42% African-American/58% Caucasian/other; mean body mass index, 29.7) with 72 tumors underwent either LRC (n = 52) or PRC (n = 20) with a mean follow-up of 30 months (median 25.1 mos; range 13-63 mos). Average patient age was 66.5 years (range 34-82 yrs). Mean tumor size was 2.33 cm (range 1-4.6 cm). Comorbid conditions were prevalent: 76% hypertension, 36% hyperlipidemia, 24% chronic kidney disease, 29% diabetes mellitus, 36% tobacco use, and 32% heart disease. RESULTS of pretreatment biopsy were 62% renal-cell carcinoma and 38% benign or nondiagnostic. Overall cancer-specific and cancer-free survival were 100% and 97%, respectively. There were two treatment failures (3.8%) in the LRC group and five primary failures in the PRC group (25%) (P = 0.015), four of which were salvaged with repeated PRC with no evidence of recurrence at 6 to 36 months of follow-up. There has been no significant local or metastatic progression. CONCLUSIONS: LRC and PRC achieved good oncologic control with minimal morbidity at a mean follow-up of 30 months in a patient cohort characterized by numerous comorbid conditions. PRC had a significantly higher primary treatment failure rate than LRC, but re-treatment offered salvage oncologic control with no significant complications.