Andrew Feifer

Combination of a novel gene expression signature with a clinical nomogram improves the prediction of survival in high-risk bladder cancer

Purpose: We aimed to validate and improve prognostic signatures for high-risk urothelial carcinoma of the bladder. Experimental Design: We evaluated microarray data from 93 patients with bladder cancer managed by radical cystectomy to determine gene expression patterns associated with clinical and prognostic variables. We compared our results with published bladder cancer microarray data sets comprising 578 additional patients and with 49 published gene signatures from multiple cancer types. Hierarchical clustering was utilized to identify subtypes associated with differences in survival. We then investigated whether the addition of survival-associated gene expression information to a validated postcystectomy nomogram utilizing clinical and pathologic variables improves prediction of recurrence. Results: Multiple markers for muscle invasive disease with highly significant expression differences in multiple data sets were identified, such as fibronectin 1 (FN1), NNMT, POSTN, and SMAD6. We identified signatures associated with pathologic stage and the likelihood of developing metastasis and death from bladder cancer, as well as with two distinct clustering subtypes of bladder cancer. Our novel signature correlated with overall survival in multiple independent data sets, significantly improving the prediction concordance of standard staging in all data sets [mean ΔC-statistic: 0.14; 95% confidence interval (CI), 0.01–0.27; P < 0.001]. Tested in our patient cohort, it significantly enhanced the performance of a postoperative survival nomogram (ΔC-statistic: 0.08, 95% CI, −0.04–0.20; P < 0.005). Conclusions: Prognostic information obtained from gene expression data can aid in posttreatment prediction of bladder cancer recurrence. Our findings require further validation in external cohorts and prospectively in a clinical trial setting. Clin Cancer Res; 18(5); 1323–33. ©2012 AACR.

Temporal trends and predictors of pelvic lymph node dissection in open or minimally invasive radical prostatectomy.

Pelvic lymph node dissection (PLND) is an important component of prostate cancer staging and treatment, especially for surgical patients who have high‐risk tumor features. It is not clear how the shift from open radical prostatectomy (ORP) to minimally invasive radical prostatectomy (MIRP) has affected the use of PLND. The objectives of this study were to identify predictors of PLND and to assess the impact of surgical technique in a contemporary, population‐based cohort.

Analytical Accuracy and Reliability of Commonly Used Nutritional Supplements in Prostate Disease

PURPOSE We determine the analytical accuracy and reliability of commonly used nutritional supplements for prostate disease by comparing the amounts of active ingredients of several brands of vitamin E, vitamin D, selenium, lycopene and saw palmetto. We also compared the amounts of active compound in different lots of the same brand to determine the consistency of the manufacturing process. MATERIALS AND METHODS Samples purchased at pharmacies and specialty stores were sent for independent chemical analysis. The measured dose was compared to the stated dose on the product label. Analysis of variance was performed to test for significance in interlot reliability. RESULTS Vitamin E (7 samples) and selenium (5) were within a range of -41% to +57% and -19% to +23% of the stated dosage, respectively. All vitamin D brands (4 samples) were within 15% of the stated dose. Saw palmetto (6 samples) were within a range -97% to +140% of the stated dosages with 3 containing less than 20% of the stated dosages. Lycopene brands were between -38% and +143% of stated dosages. Among the reliability assays 1 of 3 brands of vitamin E, 1 of 2 brands of selenium and 1 of 2 brands of saw palmetto demonstrated statistical differences in interlot dosage (p <0.0055, approximate 20% to 25% differences in dose). The 1 assayed form of vitamin D was reliable between lots. CONCLUSIONS Commonly used nutritional supplements for prostate disease vary widely in measured dose. Saw palmetto demonstrated tremendous variability with some samples containing virtually no active ingredients. In contrast, the more regulated substances we measured, such as vitamins and minerals, demonstrated less variation.

Androgen Deprivation and Thromboembolic Events in Men with Prostate Cancer

Androgen deprivation therapy (ADT) improves prostate cancer outcomes in specific clinical settings, but is associated with adverse effects, including cardiac complications and possibly thromboembolic complications. The objective of this study was to estimate the impact of ADT on thromboembolic events (TEs) in a population‐based cohort.

Maximizing Cure for Muscle-Invasive Bladder Cancer: Integration of Surgery and Chemotherapy

CONTEXT The optimal treatment strategy for muscle-invasive bladder cancer remains controversial. OBJECTIVE To determine optimal combination of chemotherapy and surgery aimed at preserving survival of patients with locally advanced bladder cancer. EVIDENCE ACQUISITION We performed a critical review of the published abstract and presentation literature on combined modality therapy for muscle-invasive bladder cancer. We emphasized articles of the highest scientific level, combining radical cystectomy and perioperative chemotherapy with curative intent to affect overall and disease-specific survival. EVIDENCE SYNTHESIS Locally invasive, regional, and occult micrometastases at the time of radical cystectomy lead to both distant and local failure, causing bladder cancer deaths. Neoadjuvant and adjuvant chemotherapy regimens have been evaluated, as well as the quality of cystectomy and pelvic lymph node dissection. CONCLUSIONS Prospective, randomized clinical trials argue strongly for neoadjuvant cisplatin-based chemotherapy followed by high-quality cystectomy performed by an experienced surgeon operating in a high-volume center. Adjuvant chemotherapy after surgery is also effective when therapeutic doses can be given in a timely fashion. Both contribute to improved overall survival; however, many patients receive only one or none of these options, and the barriers to receiving optimal, combined, systemic therapy and surgery remain to be defined. An aging, comorbid, and often unfit population increasingly affected by bladder cancer poses significant challenges in management of individual patients.

Locally advanced prostate cancer: a population-based study of treatment patterns.

Study Type – Therapy (practice patterns)

Evaluating the utility of a preoperative nomogram for predicting 90‐day mortality following radical cystectomy for bladder cancer

Study Type – Prognosis (individual cohort)

Prognostic Impact of Muscular Venous Branch Invasion in Localized Renal Cell Carcinoma Cases

PURPOSE Beginning with the 2002 American Joint Committee on Cancer staging system, renal sinus muscular venous branch invasion has prognostic equivalence with renal vein invasion in renal cell carcinoma cases. To validate this presumed equivalence we compared patients with isolated muscular venous branch invasion to those with renal vein invasion and those with no confirmed vascular invasion. MATERIALS AND METHODS From routine cataloging at our institution we identified 500 patients who underwent partial or radical nephrectomy from 2003 to 2008. After excluding patients with metastasis or noncortical renal cell carcinoma pathology we identified 85 with positive muscular venous branch invasion (+). The 259 patients with pT1-2 muscular venous branch (-) invasion and the 71 with renal vein (+) invasion served as comparison groups. We used a multivariate Cox model to control for tumor characteristics using the Kattan renal cell carcinoma nomogram. RESULTS On multivariate analysis the risk of recurrence in the pT1-2 muscular venous branch invasion (-) group was lower than in the muscular venous branch invasion (+) group (HR 0.06, 95% CI 0.02-0.18, p < 0.001). Patients with renal vein invasion (+) had a recurrence rate similar to that in those with muscular venous branch invasion (+) (HR 0.80, 95% CI 0.39-1.65, p = 0.6). The overall survival rate was higher in the muscular venous branch invasion (-) group than in the other groups. CONCLUSIONS Patients with muscular venous branch invasion have an outcome inferior to that in patients with pT1-2 disease. This confirms the adverse prognosis of muscular venous branch invasion and supports pathological up-staging. The prognosis of muscular venous branch invasion is similar to that of renal vein invasion, although we cannot exclude the possibility of a difference. Our findings underscore the importance of close patient followup and careful pathological assessment of the nephrectomy specimen.

Surgical management of renal cell carcinoma: Canadian Kidney Cancer Forum Consensus.

The Canadian Cancer Society estimated 5900 new cases of renal cell carcinoma (RCC) and 1750 related deaths in Canada in 2012.1 RCC is the sixth and eleventh most common cancer diagnosed in Canadian men and women, respectively, and its incidence has been rising by about 2.3% per year, including the period from 2005 to 2009.2 Much of this rise is attributed to incidental detection via abdominal imaging for other causes. Most of these RCCs have been small renal masses (SRMs), defined as solid-appearing masses less than 4 cm in maximum diameter.3,4 Hereditary RCC syndromes are well-described, but account for a minority of incidental findings. Other wellrecognized risk factors include cigarette smoking, obesity, hypertension and chronic renal failure.5-7

Urine Neutrophil Gelatinase-Associated Lipocalin as a Marker of Acute Kidney Injury After Kidney Surgery

PURPOSE We evaluated urine NGAL as a marker of acute kidney injury in patients undergoing partial nephrectomy. We sought to identify the preoperative clinical features and surgical factors during partial nephrectomy that are associated with renal injury, as measured by increased urine NGAL vs controls. MATERIALS AND METHODS Using patients treated with radical nephrectomy or thoracic surgery as controls, we prospectively collected and analyzed urine and serum samples from patients treated with partial or radical nephrectomy, or thoracic surgery between April 2010 and April 2012. Urine was collected preoperatively and at multiple time points postoperatively. Differences in urine NGAL levels were analyzed among the 3 surgical groups using a generalized estimating equation model. The partial nephrectomy group was subdivided based on a preoperative estimated glomerular filtration rate of less than 60, or 60 ml/minute/1.73 m(2) or greater. RESULTS Of 162 patients included in final analysis more than 65% had cardiovascular disease. The median estimated glomerular filtration rate was greater than 60 ml/minute/1.73 m(2) in the radical and partial nephrectomy, and thoracic surgery groups (61, 78 and 84.5 ml/minute/1.73 m(2), respectively). Preoperatively, a 10 unit increase in the estimated glomerular filtration rate was associated with a 4 unit decrease in urine NGAL in the partial nephrectomy group. Postoperatively, urine NGAL in the partial nephrectomy group was not higher than in controls and did not correlate with ischemia time. Patients with partial nephrectomy with a preoperative estimated glomerular filtration rate of less than 60 ml/minute/1.73 m(2) had higher urine NGAL postoperatively than those with a higher preoperative estimated rate. CONCLUSIONS Urine NGAL does not appear to be a useful marker for detecting renal injury in healthy patients treated with partial nephrectomy. However, patients with poorer preoperative renal function have higher baseline urine levels and appear more susceptible to acute kidney injury, as detected by urine levels and Acute Kidney Injury Network criteria, than those with a normal estimated glomerular filtration rate.