Leon Sun

Cancer-Specific Mortality After Surgery or Radiation for Patients With Clinically Localized Prostate Cancer Managed During the Prostate-Specific Antigen Era

PURPOSE To determine whether pretreatment risk groups shown to predict time to prostate cancer-specific mortality (PCSM) after treatment at a single institution retained that ability in a multi-institutional setting. PATIENTS AND METHODS From 1988 to 2002, 7,316 patients treated in the United States at 44 institutions with either surgery (n = 4,946) or radiation (n = 2,370) for clinical stage T1c-2, N0 or NX, M0 prostate cancer made up the study cohort. A Cox regression analysis was performed to determine the ability of pretreatment risk groups to predict time to PCSM after treatment. The relative risk (RR) of PCSM and 95% confidence intervals (CIs) were calculated for the intermediate- and high-risk groups relative to the low-risk group. RESULTS Estimates of non-PCSM 8 years after prostate-specific antigen (PSA) failure were 4% v 15% (surgery versus radiation; Plog rank =.002) compared with 13% v 18% (surgery versus radiation; Plog rank =.35) for patients whose age at the time of PSA failure was less than 70 as compared with >or= 70 years, respectively. The RR of PCSM after treatment for surgery-managed patients with high- or intermediate-risk disease was 14.2 (95% CI, 5.0 to 23.4; PCox <.0001) and 4.9 (95% CI, 1.7 to 8.1; PCox =.0037), respectively. These values were 14.3 (95% CI, 5.2 to 24.0; PCox <.0001) and 5.6 (95% CI, 2.0 to 9.3; PCox =.0012) for radiation-managed patients. CONCLUSION This study provided evidence to support the prediction of time to PCSM after surgery or radiation on the basis of pretreatment risk groups for patients with clinically localized prostate cancer managed during the PSA era.

Pathologic Variables and Recurrence Rates As Related to Obesity and Race in Men With Prostate Cancer Undergoing Radical Prostatectomy

PURPOSE To determine if obesity is associated with higher prostate specific antigen recurrence rates after radical prostatectomy (RP), and to explore racial differences in body mass index (BMI) as a potential explanation for the disparity in outcome between black and white men. PATIENTS AND METHODS A retrospective, multi-institutional pooled analysis of 3,162 men undergoing RP was conducted at nine US military medical centers between 1987 and 2002. Patients were initially categorized as obese (BMI > or = 30 kg/m(2)), overweight (BMI 25 to 30 kg/m(2)), or normal (BMI < or = 25 kg/m(2)). For analysis, normal and overweight groups were combined (BMI < 30 kg/m(2)) and compared with the obese group (BMI > or = 30 kg/m(2)) with regard to biochemical recurrence (prostate-specific antigen > or = 0.2 ng/mL) after RP. RESULTS Of 3,162 patients, 600 (19.0%) were obese and 2,562 (81%) were not obese. BMI was an independent predictor of higher Gleason grade cancer (P <.001) and was associated with a higher risk of biochemical recurrence (P =.027). Blacks had higher BMI (P <.001) and higher recurrence rates (P =.003) than whites. Both BMI (P =.028) and black race (P =.002) predicted higher prostate specific antigen recurrence rates. In multivariate analysis of race, BMI, and pathologic factors, black race (P =.021) remained a significant independent predictor of recurrence. CONCLUSION Obesity is associated with higher grade cancer and higher recurrence rates after RP. Black men have higher recurrence rates and greater BMI than white men. These findings support the hypothesis that obesity is associated with progression of latent to clinically significant prostate cancer (PC) and suggest that BMI may account, in part, for the racial variability in PC risk.

A retrospective comparison of anesthetic management of robot-assisted laparoscopic radical prostatectomy versus radical retropubic prostatectomy

STUDY OBJECTIVE To compare anesthetic management and postoperative outcomes in patients undergoing robot-assisted laparoscopic radical prostatectomy (RALP) and radical retropubic prostatectomy (RRP) with general anesthesia. DESIGN Retrospective database study of RALP and RRP patients at Duke University Medical Center from 6/2003 to 6/2006. SETTING University teaching hospital. PATIENTS 541 ASA physical status I, II, and III men, 280 of whom were RRP patients and 256 RALP patients. MEASUREMENTS Patient demographics, intraoperative fluids and blood products, hemodynamic parameters, pain scores in the Postanesthesia Care Unit (PACU), intraoperative and postoperative analgesic consumption, need for rescue antiemetics in the PACU, and intraoperative use of vasopressors and antihypertensives, were all recorded. Additional data included postoperative transfusion data; clinical status of the patients cancer preoperatively and postoperatively; hematocrit, platelet count, and creatinine levels; and length of hospital stay. MAIN RESULTS Estimated blood loss (EBL) was higher for RRP than RALP patients (mean +/- SD; 1,087 +/- 853 mL vs. 287 +/- 317 mL; P < 0.0001). Likewise, 24% of RRP patients received red blood cell (RBC) transfusions intraoperatively, compared with 0.4% RALP patients (P < 0.0001). Intraoperatively, RALP patients received more antihypertensive agents (37% vs. 21%; P < 0.0001), and fewer vasopressors (63% vs. 78%; P < 0.0001) than did RRP patients. The two groups had similar morphine-equivalent opioid use intraoperatively, but in the PACU, RALP patients required fewer morphine equivalents (mean +/- SD; 11.4 +/- 7.7 mg vs. 14.9 +/- 9.8 mg; P < 0.0001). The RALP patients had longer surgical times (mean +/- SD; 296 +/- 76 vs.193 +/- 69 min; P < 0.0001) but shorter PACU stays (mean +/- SD; 113 +/- 55 min vs. 143 +/- 58 min; P < 0.0001) and shorter hospital stays (mean +/- SD; 44 +/- 77 hrs vs. 56 +/- 26 hrs; P = 0.009). CONCLUSIONS Duration of surgery was greater with RALP, but it was associated with less EBL, fewer transfusions of blood products, and shorter PACU and hospital stays.

Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy

PURPOSE Hormonal therapy (HT) is the current mainstay of systemic treatment for prostate specific antigen (PSA) only recurrence (PSAR), however, there is virtually no published literature comparing HT to observation in the clinical setting. The goal of this study was to examine the Department of Defense Center for Prostate Disease Research observational database to compare clinical outcomes in men who experienced PSAR after radical prostatectomy by early versus delayed use of HT and by a risk stratified approach. MATERIALS AND METHODS Of 5,382 men in the database who underwent primary radical prostatectomy (RP), 4,967 patients were treated in the PSA-era between 1988 and December 2002. Of those patients 1,352 men who had PSAR (PSA after surgery greater than 0.2 ng/ml) and had postoperative followup greater than 6 months were used as the study cohort. These patients were further divided into an early HT group in which patients (355) received HT after PSA only recurrence but before clinical metastasis and a late HT group for patients (997) who received no HT before clinical metastasis or by current followup. The primary end point was the development of clinical metastases. Of the 1,352 patients with PSAR clinical metastases developed in 103 (7.6%). Patients were also stratified by surgical Gleason sum, PSA doubling time and timing of recurrence. Univariate and multivariate Cox proportional hazard models were used to evaluate the effect of early and late HT on clinical outcome. RESULTS Early HT was associated with delayed clinical metastasis in patients with a pathological Gleason sum greater than 7 or PSA doubling time of 12 months or less (Hazards ratio = 2.12, p = 0.01). However, in the overall cohort early HT did not impact clinical metastases. Race, age at RP and PSA at diagnosis had no effect on metastasis-free survival (p >0.05). CONCLUSIONS The retrospective observational multicenter database analysis demonstrated that early HT administered for PSAR after prior RP was an independent predictor of delayed clinical metastases only for high-risk cases at the current followup. Further study with longer followup and randomized trials are needed to address this important issue.

Human neutrophil activation and increased adhesion by various resuscitation fluids

Objective: To determine whether activated neutrophils play a major role in secondary tissue injury after resuscitation in trauma. We hypothesized that human neutrophil activation and adhesion vary, depending on the type and amount of resuscitation fluid used. Setting: University‐based research facility. Subjects: Ten healthy adult volunteers. Design: Whole blood from volunteers was serially diluted in polypropylene tubes with various resuscitation fluids. Fluids tested were phosphate‐buffered saline, normal saline, lactated Ringers solution, dextran, hespan, 5% human albumin, 25% human albumin, 3.5% hypertonic saline, and 7.5% hypertonic saline. Neutrophil activation (intracellular oxidative burst activity with dichlorofluorescin diacetate staining) and adhesion (integrin cell surface expression of CD18) were measured with flow cytometry (fluorescence‐activated cell sorting). Blood was diluted with hypertonic saline by controlling for sodium content equal to normal saline. Measurements and Main Results: There was a significant dose‐related increase in neutrophil oxidative burst activity as the result of dilution followed with crystalloid fluids and artificial colloids (dextran and hespan). The increase was 12‐18 × baseline at the 75% dilution. The increase with 5% human albumin was only 2.2 × baseline, and 25% albumin did not demonstrate any increased intracellular activity. A similar significant increase in the neutrophil adhesion expression (CD18) occurred with artificial colloids (p < .05) and, to a lesser extent, with crystalloids, but not with albumin. Hypertonic saline caused a decrease in CD18 cell surface expression. Conclusions: This study suggests that the neutrophil activation and adhesion may vary, depending on the type of resuscitative fluid used. All artificial resuscitative fluids may not be similar or innocuous, as demonstrated by the dose‐related increase in neutrophil activation and adhesion.

Elevated expression of PCGEM1, a prostate-specific gene with cell growth-promoting function, is associated with high-risk prostate cancer patients

PCGEM1 is a novel, highly prostate tissue-specific, androgen-regulated gene. Here, we demonstrate that PCGEM1 expression is significantly higher in prostate cancer (CaP) cells of African-American men than in Caucasian-American men (P=0.0002). Further, increased PCGEM1 expression associates with normal prostate epithelial cells of CaP patients with a family history of CaP (P=0.0400). PCGEM1 overexpression in LNCaP and in NIH3T3 cells promotes cell proliferation and a dramatic increase in colony formation, suggesting a biological role of PCGEM1 in cell growth regulation. Taken together, the cell proliferation/colony formation-promoting functions of PCGEM1 and the association of its increased expression with high-risk CaP patients suggest the potential roles of PCGEM1 in CaP onset/progression, especially in these high-risk groups.

PREDICTING RISK OF PROSTATE SPECIFIC ANTIGEN RECURRENCE AFTER RADICAL PROSTATECTOMY WITH THE CENTER FOR PROSTATE DISEASE RESEARCH AND CANCER OF THE PROSTATE STRATEGIC UROLOGIC RESEARCH ENDEAVOR DATABASES

PURPOSE Biostatistical models to predict stage or outcome in patients with clinically localized prostate cancer with pretreatment prostate specific antigen (PSA), Gleason sum on biopsy or prostatectomy specimen, clinical or pathological stage and other variables, including ethnicity, have been developed. However, to date models have relied on small subsets from academic centers or military populations that may not be representative. Our study validates and updates a model published previously with the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE, UCSF, Urology Outcomes Research Group and TAP Pharmaceutical Products, Inc.), a large multicenter, community based prostate cancer database and Center for Prostate Disease Research (CPDR), a large military database. MATERIALS AND METHODS We validated a biostatistical model that includes pretreatment PSA, highest Gleason sum on prostatectomy specimen, prostatectomy organ confinement status and ethnicity, including white and black patients. We then revised it with the Cox regression analysis of the combined 503 PSA era surgical cases from the CPDR prospective cancer database and 1,012 from the CaPSURE prostate cancer outcomes database. RESULTS The original equation with 3 risk groups stratified CaPSURE cases into distinct categories with 7-year disease-free survival rates of 72%, 42.1% and 27.6% for low, intermediate and high risk men, respectively. Parameter estimates obtained from a Cox regression analysis provided a revised model equation that calculated the relative risk of recurrence as: exponent (exp)[(0.54 x Race) + (0.05 x sigmoidal transformation of PSA [PSA(ST)]) + (0.23 x Postop Gleason) + (0.69 x Pathologic stage). The relative risk of recurrence, as calculated by the aforementioned equation, was used to stratify the cases into 4 risk groups. Very low-4.7 or less, low-4.7 to 7.1, high-7.1 to 16.7 and very high-greater than 16.7, and patients at risk had 7-year disease-free survival rates of 85.4%, 66.0%, 50.6% and 21.3%, respectively. CONCLUSIONS With a broad cohort of community based, academic and military cases, we developed an equation that stratifies men into 4 discrete risk groups of recurrence after radical prostatectomy and confirmed use of a prior 3 risk group model. Although the variables of ethnicity, pretreatment PSA, highest Gleason sum on prostatectomy specimen and organ confinement status on surgical pathology upon which the model is based are easily obtained, more refined modeling with additional variables are needed to improve prediction of intermediate risk in individuals.

Prostate cancer laterality as a rationale of focal ablative therapy for the treatment of clinically localized prostate cancer

Early detection of small‐volume prostate cancer (PCa) has led to the concept of focal therapy to treat PCa as an organ‐sparing, minimally invasive procedure. The authors sought to determine the frequency of unilateral cancers in the contemporary prostate‐specific antigen (PSA) era to determine the percentage of patients who would be candidates for hemiablation of the prostate by using focal therapy while preserving the contralateral lobe.

Obese men have higher-grade and larger tumors: an analysis of the duke prostate center database

Obesity is associated with increased risk of positive surgical margins and prostate specific antigen (PSA) recurrence among men undergoing radical prostatectomy. To what degree positive margins contribute to poorer outcome is unclear. Thus, we sought to examine the association between body mass index (BMI) and more objective measures of tumor aggressiveness, tumor grade and size. We carried out a retrospective analysis of 2302 patients treated with radical prostatectomy at the Duke Prostate Center from 1988–2007. Tumor volume was calculated by multiplying prostate weight by percent of specimen involved with cancer. Associations between BMI and tumor volume and high-grade disease (Gleason⩾4+3) independent of pre-operative clinical characteristics of age, race, PSA, clinical stage, biopsy Gleason sum, and year of surgery were assessed using linear and logistic regression, respectively. Mean and median BMI among all subjects was 28.1 and 27.6 kg m–2, respectively. Increased BMI was significantly associated with younger age (P<0.001), black race (P<0.001), more recent year of surgery (P<0.001), and positive surgical margins (P<0.001). After adjusting for multiple clinical pre-operative characteristics, higher BMI was associated with a greater percent of the prostate involved with cancer (P=0.003), increased tumor volume (P<0.001), and high-grade disease (P=0.007). Men with a BMI ⩾35 kg m2 had nearly 40% larger mean tumor volumes than normal weight men (5.1 versus 3.7 cc), after adjustment for multiple clinical characteristics. In this study, obese men undergoing radical prostatectomy had higher-grade and larger tumors, providing further evidence that obese men undergoing radical prostatectomy have more aggressive prostate cancers.

Resuscitation with lactated Ringer's solution in rats with hemorrhagic shock induces immediate apoptosis

BACKGROUND We hypothesize that different resuscitative fluids may immediately affect the degree of apoptosis after hemorrhagic shock. METHODS Rats (n = 35) were hemorrhaged 27 mL/kg over 5 minutes followed by 1 hour of shock, then resuscitation over 1 hour. The six treatment groups were sham hemorrhage, sham resuscitation, whole blood resuscitation, lactated Ringers solution (LR) resuscitation with three times the volume bled, sham hemorrhage with LR infusion, and 7.5% hypertonic saline resuscitation (9.7 mL/kg). Liver and small intestine were harvested immediately after resuscitation. Apoptosis was evaluated by using in situ cell death detection method. RESULTS Resuscitation with LR resulted in a significant increase in small intestinal and liver apoptosis. Animals that received LR infusion without hemorrhage had an increased level of apoptosis in the intestine. Apoptosis in the intestine was observed in both the mucosa and muscularis externa. There was no increase in apoptosis in either organ in the animals resuscitated with sham resuscitation, whole blood, and hypertonic saline compared with the sham hemorrhage group. CONCLUSION Resuscitation with LR solution after hemorrhagic shock increased immediate cell death by apoptosis in both the small intestine and liver. There was no significant increase in apoptosis in the animals resuscitated with hypertonic saline, whole blood, or in unresuscitated animals. Thus, the type of resuscitation fluid used may affect the apoptotic cellular response to shock.