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The Journal of urology 03/2013; · 4.02 Impact Factor
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ABSTRACT: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: No cost-effectiveness studies exist in patients after radical cystectomy for the routine use of alvimopan for the prevention of postoperative ileus. The present study provides a reasonable estimate of the cost-effectiveness of alvimopan for the prevention of postoperative ileus in the patient after radical cystectomy. OBJECTIVE: To determine if the cost of administering alvimopan, to help restore bowel function after abdominal surgery, to all patients undergoing radical cystectomy (RC) is cost prohibitive. PATIENTS AND METHODS: A cost-effective analysis was conducted from a healthcare payer perspective using a decision-tree model that incorporated direct healthcare costs and probabilities associated with the possible events and outcomes. Sensitivity analyses were conducted on the influence of the cost and effectiveness of the drug, the probability of POI in RC patients, and the extended length of stay (LOS) as a result of POI. Precision in estimates was determined using probabilistic sensitivity analyses with 5000 Monte-Carlo simulations. RESULTS: Under the base case assumption, the additional cost of a patient's LOS related to POI was $10 246 per person. Under the assumption that 15.6% of patients will have POI, the mean cost associated with POI in a cohort of patients not treated with alvimopan was $1597 (90% confidence interval [CI] $1335-1875) per patient. Conversely, the routine use of alvimopan for all patients undergoing RC was associated with a mean POI-associated cost of $1495(90% CI $1312-1696) per person, which represents the cost of alvimopan ($700 per hospitalisation) and a 50% reduction in the rate of POI. Sensitivity analyses revealed that there is a cost savings with the routine use of alvimopan under the following conditions: the POI results in extending LOS by ≥3.5 days, POI occurs in ≥14% of patients undergoing RC, or the drug results in a relative risk reduction of ≥44%. CONCLUSIONS: Routine use of perioperative alvimopan may not be cost prohibitive because of its influence on POI rate and associated costs. The cost-effectiveness of alvimopan is influenced by the POI incidence and the degree to which the drug can decrease the LOS.
BJU International 11/2012; · 2.84 Impact Factor
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ABSTRACT: PURPOSE: Robotic assisted Laparoscopic Radical Cystectomy (RARC) for bladder cancer has been reported with potential for improvement in perioperative morbidity compared to open approach. However, most studies are retrospective with significant selection bias. METHODS: A pilot prospective randomized trial evaluating perioperative outcomes and oncologic efficacy comparing ORC versus RARC for consecutive patients was performed from July 2009 to June 2011. RESULTS: To date 47 patients have been randomized with data available on 40 patients for analysis. Each group was similar with regards to age, sex, race, BMI, comorbidities, and previous surgeries, operative time, postoperative complications, and final pathologic stage. We observed no significant difference between oncologic outcomes of positive margins (5% each, p 0.50) or number of LN removed for the ORC (23, IQR 15-28) versus the RARC (11, IQR 8.75-21.5) groups respectively (p0.135). The RARC group (400 mL, IQR 300-762.5) was noted to have decreased EBL compared to the ORC group (800 mL, IQR 400-1100) and trended towards decreased rate of excessive LOS (>5 days) (65% vs. 90%, p 0.11) for the RARC versus ORC groups. The robotic group trended towards fewer transfusions (40% versus 50%, p 0.26). CONCLUSIONS: Our study validates the concept of randomizing patients with bladder cancer undergoing radical cystectomy to open or robotic approach. Our results suggest no significant differences in surrogates of oncologic efficacy. RARC demonstrates potential benefits of decreased EBL and decreased hospital stay compared to ORC. Our results need to be validated in a larger multicenter prospective randomized clinical trial.
The Journal of urology 09/2012; · 4.02 Impact Factor
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Donna P Ankerst,
Andreas Boeck,
Stephen J Freedland,
J Stephen Jones,
Angel M Cronin,
Monique J Roobol,
Jonas Hugosson,
Michael W Kattan,
Eric A Klein,
Freddie Hamdy, [......],
Helmut Klocker,
Wolfgang Horninger,
Amine Benchikh,
Gilles Salama,
Arnauld Villers,
Daniel M Moreira,
Fritz H Schröder,
Hans Lilja,
Andrew J Vickers,
Ian M Thompson
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ABSTRACT: OBJECTIVES: To assess the applicability of the Prostate Cancer Prevention Trial High Grade (Gleason grade ≥ 7) Risk Calculator (PCPTHG) in ten international cohorts, representing a range of populations. METHODS: A total of 25,512 biopsies from 10 cohorts (6 European, 1 UK and 3 US) were included; 4 implemented 6-core biopsies, and the remaining had 10 or higher schemes; 8 were screening cohorts, and 2 were clinical. PCPTHG risks were calculated using prostate-specific antigen, digital rectal examination, age, African origin and history of prior biopsy and evaluated in terms of calibration plots, areas underneath the receiver operating characteristic curve (AUC) and net benefit curves. RESULTS: The median AUC of the PCPTHG for high-grade disease detection in the 10- and higher-core cohorts was 73.5 % (range, 63.9-76.7 %) compared with a median of 78.1 % (range, 72.0-87.6 %) among the four 6-core cohorts. Only the 10-core Cleveland Clinic cohort showed clear evidence of under-prediction by the PCPTHG, and this was restricted to risk ranges less than 15 %. The PCPTHG demonstrated higher clinical net benefit in higher-core compared with 6-core biopsy cohorts, and among the former, there were no notable differences observed between clinical and screening cohorts, nor between European and US cohorts. CONCLUSIONS: The PCPTHG requires minimal patient information and can be applied across a range of populations. PCPTHG risk thresholds ranging from 5 to 20 %, depending on patient risk averseness, are recommended for clinical prostate biopsy decision-making.
World Journal of Urology 04/2012; · 2.41 Impact Factor
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ABSTRACT: Metastatic renal cancer manifests multiple signatures of gene expression. Deviation in expression of mature miRNAs has been linked to human cancers. Importance of miR-21 in renal cell carcinomas is proposed from profiling studies using tumor tissue samples. However, the role of miR-21 function in causing renal cancer cell proliferation and invasion has not yet been shown. Using cultured renal carcinoma cells, we demonstrate enhanced expression of mature miR-21 along with pre-and pri-miR-21 by increased transcription compared to normal proximal tubular epithelial cells. Overexpression of miR-21 Sponge to quench endogenous miR-21 levels inhibited proliferation, migration and invasion of renal cancer cells. In the absence of mutation in the PTEN tumor suppressor gene, PTEN protein levels are frequently downregulated in renal cancer. We show that miR-21 targets PTEN mRNA 3'untranslated region to decrease PTEN protein expression and augments Akt phosphorylation in renal cancer cells. Downregulation of PTEN as well as overexpression of constitutively active Akt kinase prevented miR-21 Sponge-induced inhibition of renal cancer cell proliferation and migration. Moreover, we show that miR-21 Sponge inhibited the inactivating phosphorylation of the tumor suppressor protein tuberin and attenuated TORC1 activation. Finally, we demonstrate that expression of constitutively active TORC1 attenuated miR-21 Sponge-mediated suppression of proliferation and migration of renal cancer cells. Our results uncover a layer of post-transcriptional regulation of PTEN by transcriptional activation of miR-21 to force the canonical oncogenic Akt/TORC1 signaling conduit to drive renal cancer cell proliferation and invasion.
PLoS ONE 01/2012; 7(6):e37366. · 4.09 Impact Factor
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ABSTRACT: Inflammatory cytokines are detected in the plasma of patients with renal cell carcinoma (RCC) and are associated with poor prognosis. However, the primary cell type involved in producing inflammatory cytokines and the biological significance in RCC remain unknown. Inflammation is associated with oxidative stress, upregulation of hypoxia inducible factor 1-alpha, and production of pro-inflammatory gene products. Solid tumors are often heterogeneous in oxygen tension together suggesting that hypoxia may play a role in inflammatory processes in RCC. Epithelial cells have been implicated in cytokine release, although the stimuli to release and molecular mechanisms by which they are released remain unclear. AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status and a role for AMPK in the regulation of cell inflammatory processes has recently been demonstrated.
We have identified for the first time that interleukin-6 and interleukin-8 (IL-6 and IL-8) are secreted solely from RCC cells exposed to hypoxia. Furthermore, we demonstrate that the NADPH oxidase isoform, Nox4, play a key role in hypoxia-induced IL-6 and IL-8 production in RCC. Finally, we have characterized that enhanced levels of IL-6 and IL-8 result in RCC cell invasion and that activation of AMPK reduces Nox4 expression, IL-6 and IL-8 production, and RCC cell invasion.
Together, our data identify novel mechanisms by which AMPK and Nox4 may be linked to inflammation-induced RCC metastasis and that pharmacological activation of AMPK and/or antioxidants targeting Nox4 may represent a relevant therapeutic intervention to reduce IL-6- and IL-8-induced inflammation and cell invasion in RCC.
PLoS ONE 01/2012; 7(1):e30712. · 4.09 Impact Factor
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Donna P Ankerst,
Andreas Boeck,
Stephen J Freedland,
Ian M Thompson,
Angel M Cronin,
Monique J Roobol,
Jonas Hugosson,
J Stephen Jones,
Michael W Kattan,
Eric A Klein, [......], Dipen J Parekh,
Helmut Klocker,
Wolfgang Horninger,
Amine Benchikh,
Gilles Salama,
Arnauld Villers,
Daniel M Moreira,
Fritz H Schröder,
Hans Lilja,
Andrew J Vickers
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ABSTRACT: To evaluate the discrimination, calibration, and net benefit performance of the Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) across five European randomized study of screening for prostate cancer (ERSPC), 1 United Kingdom, 1 Austrian, and 3 US biopsy cohorts.
PCPTRC risks were calculated for 25,733 biopsies using prostate-specific antigen (PSA), digital rectal examination, family history, history of prior biopsy, and imputation for missing covariates. Predictions were evaluated using the areas underneath the receiver operating characteristic curves (AUC), discrimination slopes, chi-square tests of goodness of fit, and net benefit decision curves.
AUCs of the PCPTRC ranged from a low of 56% in the ERSPC Goeteborg Rounds 2-6 cohort to a high of 72% in the ERSPC Goeteborg Round 1 cohort and were statistically significantly higher than that of PSA in 6 out of the 10 cohorts. The PCPTRC was well calibrated in the SABOR, Tyrol, and Durham cohorts. There was limited to no net benefit to using the PCPTRC for biopsy referral compared to biopsying all or no men in all five ERSPC cohorts and benefit within a limited range of risk thresholds in all other cohorts.
External validation of the PCPTRC across ten cohorts revealed varying degree of success highly dependent on the cohort, most likely due to different criteria for and work-up before biopsy. Future validation studies of new calculators for prostate cancer should acknowledge the potential impact of the specific cohort studied when reporting successful versus failed validation.
World Journal of Urology 12/2011; 30(2):181-7. · 2.41 Impact Factor
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Monique J Roobol,
F H Schröder,
Jonas Hugosson,
J Stephen Jones,
Michael W Kattan,
Eric A Klein,
Freddie Hamdy,
David Neal,
Jenny Donovan, Dipen J Parekh, [......],
Helmut Klocker,
Wolfgang Horninger,
Amine Benchikh,
Gilles Salama,
Arnauld Villers,
Stephen J Freedland,
Daniel M Moreira,
Andrew J Vickers,
Hans Lilja,
Ewout W Steyerberg
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ABSTRACT: To compare the predictive performance and potential clinical usefulness of risk calculators of the European Randomized Study of Screening for Prostate Cancer (ERSPC RC) with and without information on prostate volume.
We studied 6 cohorts (5 European and 1 US) with a total of 15,300 men, all biopsied and with pre-biopsy TRUS measurements of prostate volume. Volume was categorized into 3 categories (25, 40, and 60 cc), to reflect use of digital rectal examination (DRE) for volume assessment. Risks of prostate cancer were calculated according to a ERSPC DRE-based RC (including PSA, DRE, prior biopsy, and prostate volume) and a PSA + DRE model (including PSA, DRE, and prior biopsy). Missing data on prostate volume were completed by single imputation. Risk predictions were evaluated with respect to calibration (graphically), discrimination (AUC curve), and clinical usefulness (net benefit, graphically assessed in decision curves).
The AUCs of the ERSPC DRE-based RC ranged from 0.61 to 0.77 and were substantially larger than the AUCs of a model based on only PSA + DRE (ranging from 0.56 to 0.72) in each of the 6 cohorts. The ERSPC DRE-based RC provided net benefit over performing a prostate biopsy on the basis of PSA and DRE outcome in five of the six cohorts.
Identifying men at increased risk for having a biopsy detectable prostate cancer should consider multiple factors, including an estimate of prostate volume.
World Journal of Urology 12/2011; 30(2):149-55. · 2.41 Impact Factor
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ABSTRACT: With the pendulum swinging in low risk prostate cancer (PCa) to ideas of overtreatment and overdiagnosis more urologists are looking at Active Surveillance (AS) as a valid option for their low risk PCa patients. AS will undoubtedly hold a place as a management option in men with low risk PCa, however, it is critical to understand its limitations in its current form as highlighted in this article. We conducted a review of multiple computerized databases (Ovid, Medline, Pubmed, CINAHL, Cohrane Library database) with the keywords active surveillance, prostate neoplasm, and low risk PCa. Manual searches were also carried out. Assumptions of AS are discussed and their implications on selecting the appropriate AS candidate. As with any active treatment option offered to patients with PCa, those who are offered AS must be appropriately selected and counseled as to its risks and benefits.
Archivos españoles de urología 10/2011; 64(8):695-702.
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ABSTRACT: Intravesical immunotherapy using attenuated bacillus Calmette-Guérin (BCG) strains and intravesical chemotherapy are the modalities most commonly used to treat intermediate- or high-risk patients with non-muscle invasive bladder cancer. BCG has been shown to decrease recurrence rates by up to 67% compared with tumor resection alone, but intensive BCG maintenance regimens are poorly tolerated in a large proportion of patients. Intravesical chemotherapy also decreases the risk of recurrence for these patients, but has diminished efficacy compared with BCG. If BCG dose reduction can be achieved with combined intravesical immunotherapy and chemotherapy, this regimen may improve compliance and thus optimize treatment for these patients by limiting side effects from BCG monotherapy, while at the same time improving oncologic efficacy via the separate anti-tumor mechanisms of these agents. The authors discuss the most recent data regarding combining these agents in an alternating or sequential regimen.
Expert Review of Anti-infective Therapy 06/2011; 11(6):949-57. · 2.65 Impact Factor
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Urology 04/2011; 77(4):876-7. · 2.43 Impact Factor
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Nature Reviews Urology 01/2011; 8(3):126-7. · 4.41 Impact Factor
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Dipen J Parekh
Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 01/2011; 188:109-14.
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ABSTRACT: Chemoprevention for prostate cancer (PCa) continues to generate interest from both physicians and the patient population. The goal of chemoprevention is to stop the malignant transformation of prostate cells into cancer. Multiple studies on different substances ranging from supplements to medical therapy have been undertaken. Thus far, only the studies on 5 alpha-reductase inhibitors (the Prostate Cancer Prevention Trial [PCPT] and Reduction by Dutasteride of Prostate Cancer Events [REDUCE] trial) have demonstrated a reduction in the risk of PCa, while results from the Selenium and Vitamin E Cancer Prevention Trial (SELECT) concluded no decreased risk for PCa with selenium or vitamin E.
TheScientificWorldJOURNAL 01/2011; 11:742-8. · 1.66 Impact Factor
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ABSTRACT: Germline mutations of FH, the gene that encodes for the tricarboxylic acid TCA (TCA) cycle enzyme fumarate hydratase, are associated with an inherited form of cancer referred to as Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). Individuals with HLRCC are predisposed to the development of highly malignant and lethal renal cell carcinoma (RCC). The mechanisms of tumorigenesis proposed have largely focused on the biochemical consequences of loss of FH enzymatic activity. While loss of the tumor suppressor gene von Hippel Lindau (VHL) is thought to be an initiating event for the majority of RCCs, a role for FH in sporadic renal cancer has not been explored. Here we report that FH mRNA and protein expression are reduced in clear cell renal cancer, the most common histologic variant of kidney cancer. Moreover, we demonstrate that reduced FH leads to the accumulation of hypoxia inducible factor- 2α (HIF-2α), a transcription factor known to promote renal carcinogenesis. Finally, we demonstrate that overexpression of FH in renal cancer cells inhibits cellular migration and invasion. These data provide novel insights into the tumor suppressor functions of FH in sporadic kidney cancer.
PLoS ONE 01/2011; 6(6):e21037. · 4.09 Impact Factor
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Andrew J Vickers,
Angel M Cronin,
Monique J Roobol,
Jonas Hugosson,
J Stephen Jones,
Michael W Kattan,
Eric Klein,
Freddie Hamdy,
David Neal,
Jenny Donovan, [......],
George Bartsch,
Helmut Klocker,
Wolfgang Horninger,
Amine Benchikh,
Gilles Salama,
Arnauld Villers,
Steve J Freedland,
Daniel M Moreira,
Fritz H Schröder,
Hans Lilja
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ABSTRACT: The relationship between prostate-specific antigen (PSA) level and prostate cancer risk remains subject to fundamental disagreements. We hypothesized that the risk of prostate cancer on biopsy for a given PSA level is affected by identifiable characteristics of the cohort under study.
We used data from five European and three U.S. cohorts of men undergoing biopsy for prostate cancer; six were population-based studies and two were clinical cohorts. The association between PSA and prostate cancer was calculated separately for each cohort using locally weighted scatterplot smoothing.
The final data set included 25,772 biopsies and 8,503 cancers. There were gross disparities between cohorts with respect to both the prostate cancer risk at a given PSA level and the shape of the risk curve. These disparities were associated with identifiable differences between cohorts: for a given PSA level, a greater number of biopsy cores increased the risk of cancer (odds ratio for >6- versus 6-core biopsy, 1.35; 95% confidence interval, 1.18-1.54; P < 0.0005); recent screening led to a smaller increase in risk per unit change in PSA (P = 0.001 for interaction term) and U.S. cohorts had higher risk than the European cohorts (2.14; 95% confidence interval, 1.99-2.30; P < 0.0005).
Our results suggest that the relationship between PSA and risk of a positive prostate biopsy varies, both in terms of the probability of prostate cancer at a given PSA value and the shape of the risk curve. This poses challenges to the use of PSA-driven algorithms to determine whether biopsy is indicated.
Clinical Cancer Research 09/2010; 16(17):4374-81. · 7.74 Impact Factor
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ABSTRACT: Purpose of ReviewWe examine the role of chemotherapeutic agents in the prevention of prostate cancer and analyze the phase III clinical trials investigating the application of these agents for prostate cancerRecent FindingsThere are two reported phase III randomized clinical trials which evaluate the role of chemotherapeutic agents in the prevention of prostate cancer. The Prostate Cancer Prevention Trial (PCPT) originally revealed that finasteride reduced the risk of prostate cancer by approximately 25% versus placebo but patients who received finasteride had a greater incidence of high grade tumors. Recent updates of the PCPT confirmed that finasteride reduces the risk of clinically significant prostate cancer, including high-grade tumors, primarily due to improvement the performance characteristics of PSA and prostate biopsy to improve cancer detection. The SELECT trial evaluated the roles of selenium and vitamin E in the prevention of prostate cancer, but found no benefit of either supplementSummaryChemoprevention of prostate cancer is now possible with finasteride. An ancillary benefit includes an enhancement in detection of high grade, potentially fatal, prostate cancer
07/2010: pages 236 - 242; , ISBN: 9781444323146
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ABSTRACT: Mutations in the von Hippel-Lindau (VHL) gene give rise to renal cell carcinoma. Reactive oxygen species, generated by Nox oxidases, are involved in tumorigenesis. We have previously demonstrated that in VHL-deficient cells, p22(phox)-dependent Nox1 and Nox4 oxidases maintain hypoxia inducible factor-2alpha (HIF-2alpha) protein expression through an Akt-dependent translational pathway. Phosphorylation of tuberin, by Akt, results in its inactivation. Here we show that diphenyleneiodonium chloride, an inhibitor of Nox oxidases, and small-interfering RNA-mediated down-regulation of p22(phox) inhibit Akt-dependent phosphorylation of tuberin and stabilizes tuberin protein levels in VHL-deficient renal carcinoma cells. p22(phox)-mediated inactivation of tuberin is associated with an increase in ribosomal protein S6 kinase 1 and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1) phosphorylation as well as HIF-2alpha stabilization. Importantly, we find that marked up-regulation of p22(phox) in human renal cell carcinoma correlates with increased tuberin phosphorylation, decreased tuberin protein levels, and increased phosphorylation of 4E-BP1. Our data provide the first evidence that p22(phox)-based Nox oxidases maintain HIF-2alpha protein expression through inactivation of tuberin and downstream activation of ribosomal protein S6 kinase 1/4E-BP1 pathway.
American Journal Of Pathology 03/2010; 176(5):2447-55. · 4.89 Impact Factor
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ABSTRACT: Since its approval by the US FDA in 1986, prostate-specific antigen (PSA) has been employed to monitor men with a diagnosis of prostate cancer. In 1994, PSA was approved for use in prostate cancer screening and has been employed worldwide. However, due to the limited specificity of PSA for the disease, novel biomarkers are needed for detecting prostate cancer and for determining which cancers need to be treated. This review will discuss the development of new biomarkers for prostate cancer detection and disease prognostication, focusing on recent progress and particular topical issues related to the development and validation of these new markers.
Expert Review of Anti-infective Therapy 01/2010; 10(1):103-14. · 2.65 Impact Factor
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Dipen J Parekh
The Journal of urology 12/2009; 182(6):2566-8. · 4.02 Impact Factor
