Dipen J. Parekh

Randomized Prospective Evaluation of Extended Versus Limited Lymph Node Dissection in Patients With Clinically Localized Prostate Cancer

PURPOSE The low rate of pelvic node metastasis in most contemporary series of patients undergoing radical prostatectomy for carcinoma of the prostate has been attributed to earlier and better patient selection than historical series. Alternatively, it has been suggested that the limited dissection commonly performed misses nodal metastasis in a substantial number of patients. To assess the value of an extended node dissection in detecting nodal metastasis, we performed a randomized prospective study. MATERIALS AND METHODS A total of 123 patients undergoing radical prostatectomy were randomized to an extended node dissection on the right versus the left side of the pelvis with the other side being a limited dissection. The extended dissection included removal of all external iliac nodes to a point above the bifurcation of the common iliac artery, the obturator nodes and the presacral nodes. The limited dissection included only the nodes along the external iliac vein and obturator nerve. RESULTS Mean patient age was 61 years. Clinical stage was T1c in 88 patients (72%), T2a in 26 (21%), T2b in 7 (6%) and T3 in 2 (1%). Mean preoperative prostate specific antigen was 7.4 ng./ml. Pelvic lymph node metastasis was histologically confirmed in 8 patients (6.5%). Positive nodes were found on the side of the extended dissection in 4 patients, on the side of the limited dissection in 3 and on both sides in 1. Complications possibly attributable to the node dissection included lymphocele in 4 patients, lower extremity edema in 5, deep venous thrombosis in 2, ureteral injury in 1 and pelvic abscess in 1. These complications occurred 3 times more often on the side of the extended dissection (p = 0.08). CONCLUSIONS Extended node dissection in contemporary series of patients undergoing radical prostatectomy identifies few with nodal metastases not found by a more limited dissection. A trend toward an increased risk of complications attributable to the lymphadenectomy occurs with an extended dissection.

Perioperative Outcomes and Oncologic Efficacy from a Pilot Prospective Randomized Clinical Trial of Open Versus Robotic Assisted Radical Cystectomy

PURPOSE Robotic assisted laparoscopic radical cystectomy for bladder cancer has been reported with potential for improvement in perioperative morbidity compared to the open approach. However, most studies are retrospective with significant selection bias. MATERIALS AND METHODS A pilot prospective randomized trial evaluating perioperative outcomes and oncologic efficacy of open vs robotic assisted laparoscopic radical cystectomy 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 regard to age, gender, race, body mass index and comorbidities, as well as previous surgeries, operative time, postoperative complications and final pathological stage. We observed no significant differences between oncologic outcomes of positive margins (5% each, p = 0.50) or number of lymph nodes removed for open radical cystectomy (23, IQR 15-28) vs robotic assisted laparoscopic radical cystectomy (11, IQR 8.75-21.5) groups (p = 0.135). The robotic assisted laparoscopic radical cystectomy group (400 ml, IQR 300-762.5) was noted to have decreased estimated blood loss compared to the open radical cystectomy group (800 ml, IQR 400-1,100) and trended toward a decreased rate of excessive length of stay (greater than 5 days) (65% vs 90%, p = 0.11) compared to the open radical cystectomy group. The robotic group also trended toward fewer transfusions (40% vs 50%, p = 0.26). CONCLUSIONS Our study validates the concept of randomizing patients with bladder cancer undergoing radical cystectomy to an open or robotic approach. Our results suggest no significant differences in surrogates of oncologic efficacy. Robotic assisted laparoscopic radical cystectomy demonstrates potential benefits of decreased estimated blood loss and decreased hospital stay compared to open radical cystectomy. Our results need to be validated in a larger multicenter prospective randomized clinical trial.

Complications of radical cystectomy for nonmuscle invasive disease: Comparison with muscle invasive disease

PURPOSE Radical cystectomy is gold standard treatment for muscle invasive bladder cancer and is an option for many patients with nonmuscle invasive disease at high risk for disease progression. We assessed the early complications of radical cystectomy among patients with nonmuscle invasive compared to those with muscle invasive disease. MATERIALS AND METHODS We reviewed the records of 304 consecutive patients who underwent radical cystectomy from December 1995 to July 2000. We evaluated complications that occurred within 30 days of the procedure. Cases were stratified into nonmuscle invasive (PO, Pa, P1 and PIS, N0) or muscle invasive (P2-4, N0-3) tumors based on final specimen pathology. The 2 groups were then compared with respect to age, gender, race, American Society of Anesthesiologists score, type of urinary diversion, estimated blood loss, operative time and length of stay, and major and minor complications. RESULTS Of the 293 available patients 105 (36.8%) had nonmuscle invasive specimen pathology. Overall major and minor complications occurred in 4.9% and 30.4% of cases, respectively. Independent t test revealed no significant difference between groups in terms of age (p = 0.85), gender (p = 0.77), race (p = 1.0), American Society of Anesthesiologists (p = 0.32), type of urinary diversion (p = 0.33), estimated blood loss (p = 0.31), operative time (p = 0.41), length of stay (p = 0.75), or presence of major (p = 0.78) or minor (p = 0.79) complications. CONCLUSIONS The early morbidity associated with radical cystectomy for nonmuscle invasive disease is similar to but not less than that associated with muscle invasive tumors. These acceptable risks as well as the potential benefits should be discussed with patients with nonmuscle invasive bladder cancer at high risk for disease progression.

Predicting Prostate Cancer Risk Through Incorporation of Prostate Cancer Gene 3

PURPOSE The online Prostate Cancer Prevention Trial risk calculator combines prostate specific antigen, digital rectal examination, family and biopsy history, age and race to determine the risk of prostate cancer. In this report we incorporate the biomarker prostate cancer gene 3 into the Prostate Cancer Prevention Trial risk calculator. MATERIALS AND METHODS Methodology was developed to incorporate new markers for prostate cancer into the Prostate Cancer Prevention Trial risk calculator based on likelihood ratios calculated from separate case control or cohort studies. The methodology was applied to incorporate the marker prostate cancer gene 3 into the risk calculator based on a cohort of 521 men who underwent prostate biopsy with measurements of urinary prostate cancer gene 3, serum prostate specific antigen, digital rectal examination and biopsy history. External validation of the updated risk calculator was performed on a cohort of 443 European patients, and compared to Prostate Cancer Prevention Trial risks, prostate specific antigen and prostate cancer gene 3 by area underneath the receiver operating characteristic curve, sensitivity and specificity. RESULTS The AUC of posterior risks (AUC 0.696, 95% CI 0.641-0.750) was higher than that of prostate specific antigen (AUC 0.607, 95% CI 0.546-0.668, p = 0.001) and Prostate Cancer Prevention Trial risks (AUC 0.653, 95% CI 0.593-0.714, p <0.05). Although it was higher it was not statistically significantly different from that of prostate cancer gene 3 (AUC 0.665, 95% CI 0.610-0.721, p >0.05). Sensitivities of posterior risks were higher than those of prostate cancer gene 3, prostate specific antigen and Prostate Cancer Prevention Trial risks. CONCLUSIONS New markers for prostate cancer can be incorporated into the Prostate Cancer Prevention Trial risk calculator by a novel approach. Incorporation of prostate cancer gene 3 improved the diagnostic accuracy of the Prostate Cancer Prevention Trial risk calculator.

Tolerance of the Human Kidney to Isolated Controlled Ischemia

Tolerance of the human kidney to ischemia is controversial. Here, we prospectively studied the renal response to clamp ischemia and reperfusion in humans, including changes in putative biomarkers of AKI. We performed renal biopsies before, during, and after surgically induced renal clamp ischemia in 40 patients undergoing partial nephrectomy. Ischemia duration was >30 minutes in 82.5% of patients. There was a mild, transient increase in serum creatinine, but serum cystatin C remained stable. Renal functional changes did not correlate with ischemia duration. Renal structural changes were much less severe than observed in animal models that used similar durations of ischemia. Other biomarkers were only mildly elevated and did not correlate with renal function or ischemia duration. In summary, these data suggest that human kidneys can safely tolerate 30-60 minutes of controlled clamp ischemia with only mild structural changes and no acute functional loss.

Continent urinary reconstruction versus ileal conduit: a contemporary single-institution comparison of perioperative morbidity and mortality

OBJECTIVES To compare postoperative morbidity and mortality in a concurrent and contemporary series of patients who underwent radical cystectomy with ileal conduit versus orthotopic neobladder. METHODS The data of 198 patients were reviewed, 117 with orthotopic reconstruction and 81 with ileal conduit during a 5-year time frame. Thirty-day morbidity, mortality, reoperative rates, and parameters associated with the surgical procedures were obtained from chart review. RESULTS No perioperative or postoperative deaths occurred in either group. The median operative time for the ileal conduit was 201 minutes (range 140 to 373), and for the orthotopic neobladder, it was 270 minutes (range 230 to 425). The median blood loss was 389 and 474 mL, respectively. The median length of hospitalization was 8 days for the ileal conduit group and 7 days for the orthotopic neobladder group. Diversion-related complications recognized within 30 days that ultimately required a return to the operating room occurred in 3.4% of those with a neobladder and 1.2% of those with an ileal conduit. CONCLUSIONS The orthotopic neobladder is a longer and technically more complex procedure than the ileal conduit procedure. However, no demonstrable difference in morbidity or perioperative complications were found between the two procedures in our review.

The Relationship between Prostate-Specific Antigen and Prostate Cancer Risk: The Prostate Biopsy Collaborative Group

Purpose: 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. Experimental Design: 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. Results: 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). Conclusions: 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. Clin Cancer Res; 16(17); 4374–81. ©2010 AACR.

Nox4 Mediates Renal Cell Carcinoma Cell Invasion through Hypoxia-Induced Interleukin 6- and 8- Production

Background 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. Methods and Principal Findings 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. Conclusions/Significance 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.

Evaluating the PCPT risk calculator in ten international biopsy cohorts: Results from the Prostate Biopsy Collaborative Group

ObjectivesTo 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.MethodsPCPTRC 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.ResultsAUCs 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.ConclusionsExternal 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.

Functional lower urinary tract voiding outcomes after cystectomy and orthotopic neobladder.

PURPOSE We reviewed our experience with orthotopic continent urinary reconstruction after radical cystectomy to determine the functional voiding patterns and compare different methods of reservoir construction. MATERIALS AND METHODS The study included 100 consecutive patients who underwent cystectomy and orthotopic neobladder. Reservoir construction consisted of a W-shaped ileal reservoir in 40 patients, ileal reservoir with afferent limb in 26, a Padua ileal reservoir in 18, right colon in 14 and sigmoid colon in 2. The functional voiding outcome was determined by a detailed patient interview and chart review. RESULTS There were no perioperative deaths. All patients regained good daytime urinary control and none required protective pads, although 18% used protective padding at night because of nocturnal leakage. Eight patients (8%) performed self-intermittent catheterization because of poor reservoir emptying. There were no substantial differences in outcomes among the various methods of reservoir construction. CONCLUSIONS Excellent functional voiding outcomes are obtained with radical cystectomy and orthotopic bladder reconstruction. Comparable results can be achieved with use of either large bowel or ileum and with various methods of bowel folding as long as principles of preservation of the periurethral sphincter muscle, and construction of an adequate capacity and low pressure reservoir are maintained.