Danny M. Rabah

Predicting 15-Year Prostate Cancer Specific Mortality After Radical Prostatectomy

PURPOSE Long-term prostate cancer specific mortality after radical prostatectomy is poorly defined in the era of widespread screening. An understanding of the treated natural history of screen detected cancers and the pathological risk factors for prostate cancer specific mortality are needed for treatment decision making. MATERIALS AND METHODS Using Fine and Gray competing risk regression analysis we modeled clinical and pathological data, and followup information on 11,521 patients treated with radical prostatectomy at a total of 4 academic centers from 1987 to 2005 to predict prostate cancer specific mortality. The model was validated on 12,389 patients treated at a separate institution during the same period. Median followup in the modeling and validation cohorts was 56 and 96 months, respectively. RESULTS The overall 15-year prostate cancer specific mortality rate was 7%. Primary and secondary Gleason grade 4-5 (each p<0.001), seminal vesicle invasion (p<0.001) and surgery year (p=0.002) were significant predictors of prostate cancer specific mortality. A nomogram predicting 15-year prostate cancer specific mortality based on standard pathological parameters was accurate and discriminating with an externally validated concordance index of 0.92. When stratified by patient age at diagnosis, the 15-year prostate cancer specific mortality rate for pathological Gleason score 6 or less, 3+4, 4+3 and 8-10 was 0.2% to 1.2%, 4.2% to 6.5%, 6.6% to 11% and 26% to 37%, respectively. The 15-year prostate cancer specific mortality risk was 0.8% to 1.5%, 2.9% to 10%, 15% to 27% and 22% to 30% for organ confined cancer, extraprostatic extension, seminal vesicle invasion and lymph node metastasis, respectively. Only 3 of 9,557 patients with organ confined, pathological Gleason score 6 or less cancer died of prostate cancer. CONCLUSIONS Poorly differentiated cancer and seminal vesicle invasion are the prime determinants of prostate cancer specific mortality after radical prostatectomy. The prostate cancer specific mortality risk can be predicted with remarkable accuracy after the pathological features of prostate cancer are known.

Adult UrologyOncology: Prostate/Testis/Penis/UrethraPredicting 15-Year Prostate Cancer Specific Mortality After Radical Prostatectomy

PURPOSE Long-term prostate cancer specific mortality after radical prostatectomy is poorly defined in the era of widespread screening. An understanding of the treated natural history of screen detected cancers and the pathological risk factors for prostate cancer specific mortality are needed for treatment decision making. MATERIALS AND METHODS Using Fine and Gray competing risk regression analysis we modeled clinical and pathological data, and followup information on 11,521 patients treated with radical prostatectomy at a total of 4 academic centers from 1987 to 2005 to predict prostate cancer specific mortality. The model was validated on 12,389 patients treated at a separate institution during the same period. Median followup in the modeling and validation cohorts was 56 and 96 months, respectively. RESULTS The overall 15-year prostate cancer specific mortality rate was 7%. Primary and secondary Gleason grade 4-5 (each p<0.001), seminal vesicle invasion (p<0.001) and surgery year (p=0.002) were significant predictors of prostate cancer specific mortality. A nomogram predicting 15-year prostate cancer specific mortality based on standard pathological parameters was accurate and discriminating with an externally validated concordance index of 0.92. When stratified by patient age at diagnosis, the 15-year prostate cancer specific mortality rate for pathological Gleason score 6 or less, 3+4, 4+3 and 8-10 was 0.2% to 1.2%, 4.2% to 6.5%, 6.6% to 11% and 26% to 37%, respectively. The 15-year prostate cancer specific mortality risk was 0.8% to 1.5%, 2.9% to 10%, 15% to 27% and 22% to 30% for organ confined cancer, extraprostatic extension, seminal vesicle invasion and lymph node metastasis, respectively. Only 3 of 9,557 patients with organ confined, pathological Gleason score 6 or less cancer died of prostate cancer. CONCLUSIONS Poorly differentiated cancer and seminal vesicle invasion are the prime determinants of prostate cancer specific mortality after radical prostatectomy. The prostate cancer specific mortality risk can be predicted with remarkable accuracy after the pathological features of prostate cancer are known.

Survival among men with clinically localized prostate cancer treated with radical prostatectomy or radiation therapy in the prostate specific antigen era

PURPOSE Radical prostatectomy, external beam radiotherapy and brachytherapy are accepted treatments for localized prostate cancer. However, it is unknown if survival differences exist among treatments. We analyzed the survival of patients treated with these modalities according to contemporary standards. MATERIALS AND METHODS A total of 10,429 consecutive patients with localized prostate cancer treated with radical prostatectomy (6,485), external beam radiotherapy (2,264) or brachytherapy (1,680) were identified. Multivariable regression analyses were used to model the disease (biopsy grade, clinical stage, prostate specific antigen) and patient specific (age, ethnicity, comorbidity) parameters for overall survival and prostate cancer specific mortality. Propensity score analysis was used to adjust for differences in observed background characteristics. RESULTS The adjusted 10-year overall survival after radical prostatectomy, external beam radiotherapy and brachytherapy was 88.9%, 82.6% and 81.7%, respectively. Adjusted 10-year prostate cancer specific mortality was 1.8%, 2.9% and 2.3%, respectively. Using propensity score analysis, external beam radiotherapy was associated with decreased overall survival (HR 1.6, 95% CI 1.4-1.9, p<0.001) and increased prostate cancer specific mortality (HR 1.5, 95% CI 1.0-2.3, p=0.041) compared to radical prostatectomy. Brachytherapy was associated with decreased overall survival (HR 1.7, 95% CI 1.4-2.1, p<0.001) but not prostate cancer specific mortality (HR 1.3, 95% CI 0.7-2.4, p=0.5) compared to radical prostatectomy. CONCLUSIONS After adjusting for major confounders, radical prostatectomy was associated with a small but statistically significant improvement in overall and cancer specific survival. These survival differences may arise from an imbalance of confounders, differences in treatment related mortality and/or improved cancer control when radical prostatectomy is performed as initial therapy.

Nomogram Predicting Prostate Cancer–specific Mortality for Men with Biochemical Recurrence After Radical Prostatectomy

BACKGROUND The natural history of prostate-specific antigen (PSA)-defined biochemical recurrence (BCR) of prostate cancer (PCa) after definitive local therapy is highly variable. Validated prediction models for PCa-specific mortality (PCSM) in this population are needed for treatment decision-making and clinical trial design. OBJECTIVE To develop and validate a nomogram to predict the probability of PCSM from the time of BCR among men with rising PSA levels after radical prostatectomy. DESIGN, SETTING, AND PARTICIPANTS Between 1987 and 2011, 2254 men treated by radical prostatectomy at one of five high-volume hospitals experienced BCR, defined as three successive PSA rises (final value >0.2 ng/ml), single PSA >0.4 ng/ml, or use of secondary therapy administered for detectable PSA >0.1 ng/ml. Clinical information and follow-up data were modeled using competing-risk regression analysis to predict PCSM from the time of BCR. INTERVENTION Radical prostatectomy for localized prostate cancer and subsequent PCa BCR. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS PCSM. RESULTS AND LIMITATIONS The 10-yr PCSM and mortality from competing causes was 19% (95% confidence interval [CI] 16-21%) and 17% (95% CI 14-19%), respectively. A nomogram predicting PCSM for all patients had an internally validated concordance index of 0.774. Inclusion of PSA doubling time (PSADT) in a nomogram based on standard parameters modestly improved predictive accuracy (concordance index 0.763 vs 0.754). Significant parameters in the models were preoperative PSA, pathological Gleason score, extraprostatic extension, seminal vesicle invasion, time to PCa BCR, PSA level at PCa BCR, and PSADT (all p<0.05). CONCLUSIONS We constructed and validated a nomogram to predict the risk of PCSM at 10 yr among men with PCa BCR after radical prostatectomy. The nomogram may be used for patient counseling and the design of clinical trials for PCa. PATIENT SUMMARY For men with biochemical recurrence of prostate cancer after radical prostatectomy, we have developed a model to predict the long-term risk of death from prostate cancer.

Do margins matter? The influence of positive surgical margins on prostate cancer-specific mortality.

BACKGROUND Positive surgical margins (PSMs) in radical prostatectomy (RP) specimens are a frequent indication for adjuvant radiotherapy and are used as a measure of surgical quality. However, the association between PSMs and prostate cancer-specific mortality (CSM) is poorly defined. OBJECTIVE Analyze the association of PSMs with CSM, adjusting for fixed and time-dependent parameters. DESIGN, SETTING, AND PARTICIPANTS Fine and Gray competing risk regression analysis was used to model the clinical data and follow-up information of 11,521 patients treated by RP between 1987 and 2005. Two extended models were used that adjusted for the use of postoperative radiotherapy, which was handled as a time-dependent covariate. Postoperative radiotherapy was modeled as a single parameter and also as early and late therapy, based on the prostate-specific antigen level at the start of treatment (≤0.5 vs >0.5 ng/ml). INTERVENTION RP for clinically localized prostate cancer and selective use of secondary local and/or systemic therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The outcome measure was prostate cancer-specific mortality. RESULTS AND LIMITATIONS The 15-yr CSM rates for patients with PSMs and negative surgical margins were 10% and 6%, respectively (p<0.001). No significant association between PSM and CSM was observed in the conventional model with fixed covariates (hazard ratio [HR]: 1.04; 95% confidence interval [CI], 0.7-1.5; p=0.8) or in the two extended models that adjusted for postoperative radiotherapy (HR: 0.96; 95% CI, 0.7-1.4; p=0.9), or early and late postoperative radiotherapy (HR: 1.01; 95% CI, 0.7-1.4; p=0.9). CONCLUSIONS PSMs alone are not associated with a significantly increased risk of CSM within 15 yr of RP. However, urologists should continue to strive to avoid PSMs, as they increase a mans risk of biochemical recurrence and need for secondary therapy and may be a source of considerable patient anxiety.

Enhanced anticancer efficacy of snake venom combined with silica nanoparticles in a murine model of human multiple myeloma: molecular targets for cell cycle arrest and apoptosis induction.

Multiple myeloma (MM) is a clonal disease of plasma cells that reside in the bone marrow (BM). MM is an incurable disease; thus, screening for novel anti-myeloma drugs remains critically important. We recently described a silica nanoparticle-based snake venom delivery model that targets cancer cells, but not normal cells. Using this model, we demonstrated a strong enhancement of the antitumor activity of snake venom extracted from Walterinnesia aegyptia (WEV) in two breast carcinoma cell lines when the venom was combined with silica nanoparticles (WEV+NP). In the present study, we aimed to delineate the in vivo therapeutic efficacy of WEV+NP in an MM-bearing experimental nude mouse model. We found that treatment with WEV+NP or WEV alone significantly inhibited tumor growth compared to treatment with NP or vehicle. WEV+NP- and WEV-treated cancer cells exhibited marked elevations in oxidative stress and robust reductions in the levels of interleukin-6 (IL-6) and B cell-activating factor (BAFF). WEV+NP also decreased the surface expression of the chemokine receptors CXCR3, CXCR4 and CXCR6 to a greater extent than WEV alone, and WEV+NP subsequently reduced migration in response to the cognate ligands CXCL10, CXCL12 and CXCL16. Furthermore, we found that WEV+NP strongly inhibited insulin-like growth factor 1 (EGF-1)- and IL-6-mediated MM cell proliferation, altered the cell cycle and enhanced the induction of apoptosis of MM cells. In addition, the results of treatment with WEV+NP or WEV alone revealed that the combination of WEV with NP robustly decreased the expression of cyclin D1, Bcl-2 and the phosphorylation of AKT; increased the expression of cyclin B1; altered the mitochondrial membrane potential; increased the activity of caspase-3, -8 and -9; and sensitized MM cells to growth arrest and apoptosis. Our data reveal the therapeutic potential of the nanoparticle-sustained delivery of snake venom to fight cancer cells.

Induction of Apoptosis and Growth Arrest in Human Breast Carcinoma Cells by a Snake (Walterinnesia aegyptia) Venom Combined With Silica Nanoparticles: Crosstalk Between Bcl2 and Caspase 3

We recently demonstrated that the snake venom extracted from Walterinnesia aegyptia (WEV) either alone or combined with silica nanoparticles (WEV+NP) enhanced the proliferation of mice immune cells and simultaneously decreased the proliferation of human breast carcinoma cell line (MDA-MB-231). However, the molecular mechanism of how this venom induced growth arrest of breast cancer cells has not been studied. In this context, we extended our study to evaluate the anti-tumor potential of WEV and WEV+NP on the human breast carcinoma cell lines MDA-MB-231 and MCF-7, as well as their effects on non-tumorigenic normal breast epithelial cells (MCF-10). The IC50 values of WEV alone and WEV+NP in these cell lines were determined to be 50 ng/ml and 20 ng/ml, respectively. Interestingly, at these concentrations, the venom did not affect the viability of normal MCF-10 cells and treatment of all these cell lines with NP alone did not affect their viability. Using annexin-V binding assay followed by flow cytometry analysis, we found that combination of WEV with NP strongly induced apoptosis in MDA-MB-231 and MCF-7 cancer cells without significant effect on normal MCF-10 cells. Furthermore, we found that WEV+NP decreased the expression of Bcl2 and enhanced the activation of caspase 3 in MDA-MB-231 and MCF-7 cells. Most importantly, WEV+NP-treated breast cancer cells, but not normal MCF-10 cells, exhibited a significant (P<0.05) reduction in actin polymerization and cytoskeletal rearrangement in response to CXCL12. Our data reveal biological effects of WEV or WEV+NP and the underlying mechanisms to fight breast cancer cells.

Treatment of diabetic mice with undenatured whey protein accelerates the wound healing process by enhancing the expression of MIP-1α, MIP-2, KC, CX3CL1 and TGF-β in wounded tissue

BackgroundContinuous diabetes-associated complications are a major source of immune system exhaustion and an increased incidence of infection. Diabetes can cause poor circulation in the feet, increasing the likelihood of ulcers forming when the skin is damaged and slowing the healing of the ulcers. Whey proteins (WPs) enhance immunity during childhood and have a protective effect on some immune disorders. Therefore, in this study, we investigated the effects of camel WP on the healing and closure of diabetic wounds in a streptozotocin (STZ)-induced type I diabetic mouse model.ResultsDiabetic mice exhibited delayed wound closure characterized by a significant decrease in an anti-inflammatory cytokine (namely, IL-10) and a prolonged elevation of the levels of inflammatory cytokines (TNF-α, IL-1β and IL-6) in wound tissue. Moreover, aberrant expression of chemokines that regulate wound healing (MIP-1α, MIP-2, KC and CX3CL1) and growth factors (TGF-β) were observed in the wound tissue of diabetic mice compared with control nondiabetic mice. Interestingly, compared with untreated diabetic mice, supplementation with WP significantly accelerated the closure of diabetic wounds by limiting inflammatory stimuli via the restoration of normal IL-10, TNF-α, IL-1β and IL-6 levels. Most importantly, the supplementation of diabetic mice with WP significantly modulated the expression of MIP-1α, MIP-2, KC, CX3CL1 and TGF-β in wound tissue compared with untreated diabetic mice.ConclusionOur data demonstrate the benefits of WP supplementation for improving the healing and closure of diabetic wounds and restoring the immune response in diabetic mice.

Therapeutic efficacy and molecular mechanisms of snake (Walterinnesia aegyptia) venom-loaded silica nanoparticles in the treatment of breast cancer- and prostate cancer-bearing experimental mouse models.

The treatment of drug-resistant cancer is a clinical challenge, and thus screening for novel anticancer drugs is critically important. We recently demonstrated a strong enhancement of the antitumor activity of snake (Walterinnesia aegyptia) venom (WEV) in vitro in breast carcinoma, prostate cancer, and multiple myeloma cell lines but not in normal cells when the venom was combined with silica nanoparticles (WEV+NP). In the present study, we investigated the in vivo therapeutic efficacy of WEV+NP in breast cancer- and prostate cancer-bearing experimental mouse models. Xenograft breast and prostate tumor mice models were randomized into 4 groups for each cancer model (10 mice per group) and were treated with vehicle (control), NP, WEV, or WEV+NP daily for 28 days post tumor inoculation. The tumor volumes were monitored throughout the experiment. On Day 28 post tumor inoculation, breast and prostate tumor cells were collected and either directly cultured for flow cytometry analysis or lysed for Western blot and ELISA analysis. Treatment with WEV+NP or WEV alone significantly reduced both breast and prostate tumor volumes compared to treatment with NP or vehicle alone. Compared to treatment with WEV alone, treatment of breast and prostate cancer cells with WEV+NP induced marked elevations in the levels of reactive oxygen species (ROS), hydroperoxides, and nitric oxide; robust reductions in the levels of the chemokines CXCL9, CXCL10, CXCL12, CXCL13, and CXCL16 and decreased surface expression of their cognate chemokine receptors CXCR3, CXCR4, CXCR5, and CXCR6; and subsequent reductions in the chemokine-dependent migration of both breast and prostate cancer cells. Furthermore, we found that WEV+NP strongly inhibited insulin-like growth factor 1 (IGF-1)- and epidermal growth factor (EGF)-mediated proliferation of breast and prostate cancer cells, respectively, and enhanced the induction of apoptosis by increasing the activity of caspase-3,-8, and -9 in both breast and prostate cancer cells. In addition, treatment of breast and prostate cancer cells with WEV+NP or WEV alone revealed that the combination of WEV with NP robustly decreased the phosphorylation of AKT, ERK, and IκBα; decreased the expression of cyclin D1, surviving, and the antiapoptotic Bcl-2 family members Bcl-2, Bcl-XL, and Mcl-1; markedly increased the expression of cyclin B1 and the proapoptotic Bcl-2 family members Bak, Bax, and Bim; altered the mitochondrial membrane potential; and subsequently sensitized tumor cells to growth arrest. Our data reveal the therapeutic potential of the nanoparticle-sustained delivery of snake venom against different cancer cell types.

Prospective randomized trial of 100u vs 200u botox in the treatment of idiopathic overactive bladder

Aim: To evaluate the clinical outcomes of two different doses of BTX-A in patients with refractory idiopathic overactive bladder. Patients and Methods: Thirty nine patients with refractory idiopathic overactive bladder from 1/1/2008 till 30/3/2009 were evaluated in a tertiary care hospital. Patients were evaluated using urodynamic studies, voiding diary, UDI-6 and IIQ-7 questionnaires prior to being prospectively randomized (alternate randomization) to the BTX-A applications and three months after treatment. Voiding diary and residual volume were followed two weeks later. All patients received intradetrusorial injections of BTX-A (Botox, Allergan, Irvine, CA) of 100u or 200u under cystoscopic control on an outpatient basis. The primary endpoint was assessed for the improvement of urodynamic parameters and adverse events at three months after the initial treatment. Secondary end points included urinary frequency, urgency and UUI episodes as assessed by voiding diary and QoL. Results: Eleven patients were enrolled to each arm of the study. There were no significant differences in demographic characteristics between the two groups. Urodynamic assessment at the end of the third month showed significant improvement in urodynamic variables in both groups. There was no statistically significant difference in urodynamic parameters and in the voiding diary between the two groups. QOL was significantly improved in both groups with no statistically significant difference between the different doses. Only three patients developed acute urinary retention. Conclusion: BTX-A at 100u and 200u appears to improve symptoms, urodynamic parameters and QoL with no statistical significance between the two groups.