Stephanie Daignault

Partial Nephrectomy for Small Renal Masses: An Emerging Quality of Care Concern?

PURPOSE The recent popularization of laparoscopic radical nephrectomy may beget underuse of partial nephrectomy. To evaluate this concern we used the SEER registry to characterize national practice patterns for the surgical management of small renal masses. MATERIALS AND METHODS Between 1988 and 2001, 14,647 patients with primary tumor size 7 cm or less were treated surgically for locoregional kidney cancer. The proportion of patients treated with PN was determined and stratified by year of diagnosis and tumor size. Multivariate models were developed to identify independent determinants of PN use and overall survival following surgical treatment of kidney cancer. RESULTS Overall 1,401 patients (9.6%) were treated with PN vs 13,246 (90.4%) who underwent total nephrectomy. For tumors 7 cm or less, the use of PN increased progressively between 1988 (4.6%) and 2001 (17.6%, p < 0.001). Despite this trend PN remained fairly uncommon even for the smallest renal masses. Among patients with tumors less than 2 cm, 14% underwent PN in 1988 to 1989 vs 42% in 2000 to 2001. For tumors 2 to 4 cm the corresponding proportions were 5% and 20%, respectively (p < 0.001). Younger patient age, smaller tumor size and more recent diagnostic year were independent determinants of PN use (all p values < 0.05). All cause mortality was similar for patients treated with PN vs TN (HR 0.9, 95% CI 0.8-1.1). CONCLUSIONS Despite more frequent application during the last 2 decades, nationwide use of PN remains relatively uncommon, even for the smallest renal masses. Recognizing the favorable outcomes associated with preservation of renal parenchyma, our findings identify a possible quality of care concern that should be addressed by the urological community.

Long-term durability and functional outcomes among patients with artificial urinary sphincters: a 10-year retrospective review from the University of Michigan.

PURPOSE The artificial urinary sphincter continues to be one of the most effective and commonly used surgical treatments for severe urinary incontinence. The long-term durability and functional outcome remains unclear. This study sought to report the artificial urinary sphincter complication rates, associated risk factors with complications, and long-term quality of life and durability. MATERIALS AND METHODS This single institution study reports the outcomes of 124 consecutive index cases of artificial urinary sphincter from 1996 to 2006 for complications (infection, erosion, and mechanical failure). Bivariate statistics and multivariable logistic models were used to identify patient and artificial urinary sphincter characteristics associated with complications. Functional outcomes and long-term durability were assessed using a cross sectional analysis of a validated health related quality of life survey and a product limit estimates, respectively. RESULTS Among the 124 male patients median followup was 6.8 years. The overall complication rate for patients undergoing an artificial urinary sphincter was 37.0%, with mechanical failure the most common cause (29), followed by erosion (10) and then infection (7). Significant differences between complications and specific patient and artificial urinary sphincter characteristics risk factors were not found. Functional outcomes appeared stable with similar mild-moderate urinary incontinence severity and 0 to 1 daily pad use at intervals of 0 to 4 years, 4 to 8 years and more than 8 years. Long-term durability was notable with 36% having complications (requiring surgical revision or removal) within 10 years and most events occurring within the first 48 months. CONCLUSIONS Long-term durability and functional outcomes are achievable for the AMS 800, but there are appreciable complication rates for erosion, mechanical failure and infection in the first 48 months from implantation.

Five-year survival after surgical treatment for kidney cancer: a population-based competing risk analysis.

Kidney cancers rising incidence is largely attributable to the increased detection of small renal masses. Although surgery rates have paralleled this incidence trend, mortality continues to rise, calling into question the necessity of surgery for all patients with renal masses. Using a population‐based cohort, a competing risk analysis was performed to estimate patient survival after surgery for kidney cancer, as a function of patient age and tumor size at diagnosis.

HER2 Drives Luminal Breast Cancer Stem Cells in the Absence of HER2 Amplification: Implications for Efficacy of Adjuvant Trastuzumab

Although current breast cancer treatment guidelines limit the use of HER2-blocking agents to tumors with HER2 gene amplification, recent retrospective analyses suggest that a wider group of patients may benefit from this therapy. Using breast cancer cell lines, mouse xenograft models and matched human primary and metastatic tissues, we show that HER2 is selectively expressed in and regulates self-renewal of the cancer stem cell (CSC) population in estrogen receptor-positive (ER(+)), HER2(-) luminal breast cancers. Although trastuzumab had no effects on the growth of established luminal breast cancer mouse xenografts, administration after tumor inoculation blocked subsequent tumor growth. HER2 expression is increased in luminal tumors grown in mouse bone xenografts, as well as in bone metastases from patients with breast cancer as compared with matched primary tumors. Furthermore, this increase in HER2 protein expression was not due to gene amplification but rather was mediated by receptor activator of NF-κB (RANK)-ligand in the bone microenvironment. These studies suggest that the clinical efficacy of adjuvant trastuzumab may relate to the ability of this agent to target the CSC population in a process that does not require HER2 gene amplification. Furthermore, these studies support a CSC model in which maximal clinical benefit is achieved when CSC targeting agents are administered in the adjuvant setting. Cancer Res; 73(5); 1635-46. ©2012 AACR.

Cystectomy Delay More Than 3 Months From Initial Bladder Cancer Diagnosis Results in Decreased Disease Specific and Overall Survival

PURPOSE Some groups hypothesize that a delay in cystectomy may result in higher pathological stage and possibly alter survival in patients with bladder cancer. The timing of this delay has been somewhat arbitrary. We evaluated the timing from T2 bladder cancer diagnosis to cystectomy, its impact on survival and potential causes of delay. MATERIALS AND METHODS A contemporary cohort of 214 consecutive patients presented with clinical T2 bladder cancer and underwent radical cystectomy as primary therapy. Clinicopathological parameters were maintained in an institutional database. A review of time to cystectomy, pathological stage, disease specific survival and OS was performed. Variables were tested in univariate and multivariate analyses. The log rank test was used for exploratory analyses to determine meaningful delay cutoff points. RESULTS Mean followup and time to cystectomy in the entire cohort was 40 months and 60 days, respectively. A significant disease specific survival and OS advantage was observed in patients undergoing cystectomy by 93 days or less (3.1 months) compared to greater than 93 days (p = 0.05 and 0.02, respectively). Pathological staging was similar between the groups (p = 0.15). A multivariate benefit in OS was observed in patients treated with timely cystectomy. The most common factor contributing to cystectomy delay was scheduling delay, as seen in 46% of cases. CONCLUSIONS A cystectomy delay of 3.1 months undermines patient survival, likely through the development of micrometastases, since local stage progression is not apparent at this point. Most delays are avoidable and should be minimized. Despite the need for second opinions and the impact of busy surgical schedules clinicians must strive to schedule patients efficiently and complete surgical treatment within this time frame.

Volume-Based Referral for Cancer Surgery: Informing the Debate

PURPOSE Mounting evidence suggests a relationship between hospital volume and outcomes after major cancer surgery; however, the absolute benefits of volume-based referral on a national basis are unclear. PATIENTS AND METHODS Data from the Nationwide Inpatient Sample were used to measure the likelihood of operative mortality and a prolonged length of stay (LOS) after six cancer surgeries (prostatectomy, cystectomy, esophagectomy, pancreatectomy, pneumonectomy, and liver resection) between 1993 and 2003. Using sampling weights, the adjusted likelihood of the outcomes was used to calculate the number of lives saved (or prolonged LOS avoided) in the United States. RESULTS The magnitude of the volume-operative mortality effect varied from an adjusted odds ratio (OR) of 1.3 (95% CI, 0.8 to 2.3) for cystectomy to 4.9 (95% CI, 2.4 to 10.1) for pancreatectomy. After accounting for varying rates of procedure utilization, the lives saved per 100 surgeries regionalized ranged from 0.2 (95% CI, 0.12 to 0.24 lives saved) for prostatectomy to 9.2 (95% CI, 6.7 to 10.4 lives saved) for pancreatectomy. The volume-prolonged LOS effect varied from an adjusted OR of 0.9 (95% CI, 0.5 to 1.6) for liver resection to 4.8 (95% CI, 3.5 to 6.7) for prostatectomy. After accounting for procedure use, the number of prolonged hospitalizations avoided ranged from -1.7 (95% CI, -11.3 to 3.6 hospitalizations) to 14.3 (95% CI, 12.9 to 15.4 hospitalizations) per 100 surgeries regionalized for liver resection and prostatectomy, respectively. CONCLUSION For patients undergoing major cancer surgery, the benefits of volume-based referral depend on the interplay between procedure utilization, the magnitude of effect, and the outcome chosen.

Polycomb Protein EZH2 Regulates Tumor Invasion via the Transcriptional Repression of the Metastasis Suppressor RKIP in Breast and Prostate Cancer

Epigenetic modifications such as histone methylation play an important role in human cancer metastasis. Enhancer of zeste homolog 2 (EZH2), which encodes the histone methyltransferase component of the polycomb repressive complex 2 (PRC2), is overexpressed widely in breast and prostate cancers and epigenetically silences tumor suppressor genes. Expression levels of the novel tumor and metastasis suppressor Raf-1 kinase inhibitor protein (RKIP) have been shown to correlate negatively with those of EZH2 in breast and prostate cell lines as well as in clinical cancer tissues. Here, we show that the RKIP/EZH2 ratio significantly decreases with the severity of disease and is negatively associated with relapse-free survival in breast cancer. Using a combination of loss- and gain-of-function approaches, we found that EZH2 negatively regulated RKIP transcription through repression-associated histone modifications. Direct recruitment of EZH2 and suppressor of zeste 12 (Suz12) to the proximal E-boxes of the RKIP promoter was accompanied by H3-K27-me3 and H3-K9-me3 modifications. The repressing activity of EZH2 on RKIP expression was dependent on histone deacetylase promoter recruitment and was negatively regulated upstream by miR-101. Together, our findings indicate that EZH2 accelerates cancer cell invasion, in part, via RKIP inhibition. These data also implicate EZH2 in the regulation of RKIP transcription, suggesting a potential mechanism by which EZH2 promotes tumor progression and metastasis.

Dickkopf-1 expression increases early in prostate cancer development and decreases during progression from primary tumor to metastasis

Prostate cancer (PCa) frequently metastasizes to the bone and induces osteoblastic lesions. We previously demonstrated through over‐expression of the Wnt inhibitor dickkopf‐1 (DKK‐1) that Wnts contribute to the osteoblastic component of PCa osseous lesions in vivo.

Patterns of Hematuria Referral to Urologists: Does a Gender Disparity Exist?

OBJECTIVES To examine the referral patterns of hematuria within a nonprofit healthcare organization to determine the factors that influence referral. Hematuria continues to be an important sign of urologic disease, including urothelial malignancy. An increasing awareness of gender differences in tumor stage at bladder cancer presentation has led to speculation about delayed referral and diagnosis in women. However, little is known about the referral patterns of hematuria and whether gender differences exist. METHODS The insurance records were examined from 926 consecutive adult health plan participants (559 men and 367 women) with newly diagnosed hematuria from 1998 to 2002. The patterns of urologic referral were evaluated. A Cox multivariate regression model was used to examine the relationship between urologic referral and the relevant variables. RESULTS Overall, 263 men (47%) and 102 women (28%) were referred for urologic evaluation of hematuria, with a median follow-up of 27 and 26 months, respectively. Referral was initiated by the primary care physician in 80% of the cohort. Increased urologic referral was associated with advancing age, repeated hematuria, provider type, and male gender. The adjusted hazard ratio of male referral was 1.65 (95% confidence interval 1.31-2.08) compared with female referral. CONCLUSIONS Primary care physicians practicing in a managed care setting are less likely to refer women for a urologic evaluation of new or first recurrent episodes of hematuria than to refer men in all patient age categories, except for 40-49 years. This apparent gender disparity could result in unequal access of specialty evaluation and could potentially delay the diagnosis of important urologic conditions.

Elevated E2F1 inhibits transcription of the androgen receptor in metastatic hormone-resistant prostate cancer

Activation of E2F transcription factors, through disruption of the retinoblastoma (Rb) tumor-suppressor gene, is a key event in the development of many human cancers. Previously, we showed that homozygous deletion of Rb in a prostate tissue recombination model exhibits increased E2F activity, activation of E2F-target genes, and increased susceptibility to hormonal carcinogenesis. In this study, we examined the expression of E2F1 in 667 prostate tissue cores and compared it with the expression of the androgen receptor (AR), a marker of prostate epithelial differentiation, using tissue microarray analysis. We show that E2F1 expression is low in benign and localized prostate cancer, modestly elevated in metastatic lymph nodes from hormone-naïve patients, and significantly elevated in metastatic tissues from hormone-resistant prostate cancer patients (P = 0.0006). In contrast, strong AR expression was detected in benign prostate (83%), localized prostate cancer (100%), and lymph node metastasis (80%), but decreased to 40% in metastatic hormone-resistant prostate cancer (P = 0.004). Semiquantitative reverse transcription-PCR analysis showed elevated E2F1 mRNA levels and increased levels of the E2F-target genes dihyrofolate reductase and proliferating cell nuclear antigen in metastatic hormone-independent prostate cancer cases compared with benign tissues. To identify a role of E2F1 in hormone-independent prostate cancer, we examined whether E2F1 can regulate AR expression. We show that exogenous expression of E2F1 significantly inhibited AR mRNA and AR protein levels in prostate epithelial cells. E2F1 also inhibited an AR promoter-luciferase construct that was dependent on the transactivation domain of E2F1. Furthermore, using chromatin immunoprecipitation assays, we show that E2F1 and the pocket protein family members p107 and p130 bind to the AR promoter in vivo. Taken together, these results show that elevated E2F1, through its ability to repress AR transcription, may contribute to the progression of hormone-independent prostate cancer.