Ahmed Magheli

Impact of surgical technique (open vs laparoscopic vs robotic-assisted) on pathological and biochemical outcomes following radical prostatectomy: an analysis using propensity score matching

Study Type – Therapy (case series)

Erectile dysfunction following prostatectomy: prevention and treatment

Radical prostatectomy (RP) remains the standard treatment for men with clinically localized prostate cancer, despite the range of alternative treatment modalities. Even with significant advances in surgical technique and superb results for cancer control and preservation of urinary function, erectile dysfunction (ED) following RP is a common complication. This is mainly attributed to temporary cavernous nerve damage (neuropraxia) resulting in penile hypoxia, smooth muscle apoptosis, fibrosis and veno-occlusive dysfunction. One of the most promising new approaches is the concept of early penile rehabilitation, which is thought to prevent ED after RP by countering post-RP pathophysiological changes during the period of neural recovery. Various treatments, such as vacuum constriction devices, intraurethral and intracorporal alprostadil, and phosphodiesterase type 5 (PDE5) inhibitors, might serve to facilitate recovery of erectile function. PDE5 inhibitors are considered as the first-line treatment for early penile rehabilitation, with superior erectile function outcomes compared to placebo. Definitive conclusions regarding the success of penile rehabilitation cannot be drawn at this time because of differences in study design, data acquisition, and definitions of potency. Continued prospective, rigorous study is needed to develop and bring forward this important field and to establish the best evidence basis for counseling and treating patients suffering from ED after RP.

Tertiary Gleason Patterns and Biochemical Recurrence After Prostatectomy: Proposal for a Modified Gleason Scoring System

PURPOSE We investigated the relationship between the tertiary Gleason component in radical prostatectomy specimens and biochemical recurrence in what is to our knowledge the largest single institution cohort to date. MATERIALS AND METHODS We evaluated data on 3,230 men who underwent radical prostatectomy at our institution from 2000 to 2005. Tertiary Gleason component was defined as Gleason grade pattern 4 or greater for Gleason score 6 and Gleason grade pattern 5 for Gleason score 7 or 8. RESULTS Biochemical recurrence curves for cancer with tertiary Gleason component were intermediate between those of cancer without a tertiary Gleason component in the same Gleason score category and cancer in the next higher Gleason score category. The only exception was that Gleason score 4 + 3 = 7 with a tertiary Gleason component behaved like Gleason score 8. The tertiary Gleason component independently predicted recurrence when factoring in radical prostatectomy Gleason score, radical prostatectomy stage and prostate specific antigen (HR 1.45, p = 0.029). Furthermore, the magnitude of the tertiary Gleason component effect on recurrence did not differ by Gleason score category (p = 0.593). CONCLUSIONS Although the tertiary Gleason component is frequently included in pathology reports, it is routinely omitted in other situations, such as predictive nomograms, research studies and patient counseling. The current study adds to a growing body of evidence highlighting the importance of the tertiary Gleason component in radical prostatectomy specimens. Accordingly consideration should be given to a modified radical prostatectomy Gleason scoring system that incorporates tertiary Gleason component in intuitive fashion, including Gleason score 6, 6.5 (Gleason score 6 with tertiary Gleason component), 7 (Gleason score 3 + 4 = 7), 7.25 (Gleason score 3 + 4 = 7 with tertiary Gleason component), 7.5 (Gleason score 4 + 3), 8 (Gleason score 4 + 3 with tertiary Gleason component or Gleason score 8), 8.5 (Gleason score 8 with tertiary Gleason component), 9 (Gleason score 4 + 5 or 5 + 4) and 10.

Impact of Body Mass Index on Biochemical Recurrence Rates After Radical Prostatectomy: An Analysis Utilizing Propensity Score Matching

OBJECTIVES To investigate the significance of body mass index (BMI) as an independent predictor of biochemical recurrence in men treated with surgery for clinically localized adenocarcinoma of the prostate. METHODS A total of 1877 obese patients who underwent radical prostatectomy were matched to overweight and normal-weight patients in a 1:1 ratio on the basis of propensity scores. This resulted in an overall study population of 5631 men. Clinicopathologic characteristics and biochemical recurrence outcomes after surgery were compared between the three BMI cohorts. RESULTS Normal-weight patients exhibited lower-grade disease compared with overweight and obese patients (P = 0.021). Lower BMI was also significantly associated with lower rates of positive surgical margins (P <0.001) and extraprostatic extension (P <0.001). Body mass index was not associated with lymph node involvement (P = 0.226) or seminal vesicle invasion (P = 0.142). Body mass index, age, biopsy Gleason score, preoperative prostate-specific antigen level, and clinical tumor stage were independent predictors of biochemical recurrence (P <0.001). CONCLUSIONS Propensity score-based matched analyses indicate that higher BMI is associated with adverse pathologic findings and is a strong independent predictor of biochemical recurrence after radical prostatectomy. These results support the hypothesis that inherent differences may exist in the biological properties of prostate cancer in obese men compared with normal-weight men. Therefore, BMI is an important criterion to consider during subsequent decision making and counseling of patients with prostate cancer.

Sequence Therapy in Patients with Metastatic Renal Cell Carcinoma: Comparison of Common Targeted Treatment Options Following Failure of Receptor Tyrosine Kinase Inhibitors

BACKGROUND The best sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been sufficiently defined. OBJECTIVE To describe the efficacy and toxicity of sequential everolimus (EV) versus receptor tyrosine kinase inhibitor (rTKI) following failure of first rTKI treatment. DESIGN, SETTING, AND PARTICIPANTS Retrospective study of 108 patients receiving rTKI or EV after progression on rTKI therapy at two German academic centres. INTERVENTION Sequence of systemic targeted treatment with sunitinib (n=85) or sorafenib (n=23) followed by EV (n=62) or another rTKI (n=46; sorafenib, n=35; sunitinib, n=11). MEASUREMENTS We measured response rate (Response Evaluation Criteria in Solid Tumours 1.0) and toxicity. Survival analysis (Kaplan-Meier method and Cox regression) was conducted for progression-free survival (PFS) and overall survival (OS). RESULTS AND LIMITATIONS Main patient characteristics did not significantly differ by sequence of treatment groups (rTKI-rTKI vs rTKI-EV). Response rate following first rTKI failure was not significantly different between sequential therapies with a disease control rate of 51.6% (EV) and 43.5% (rTKI). The corresponding median PFS was 3.6 mo (95% confidence interval [CI], 1.8-5.4) for EV and 4.0 mo (3.2-4.9) for rTKI treatment. The estimated OS was longer for the rTKI-EV group (43 mo; 95% CI, 33.9-52.1) than for the rTKI-rTKI group (29 mo; 95% CI, 18.6-39.5; p=0.03), but this difference lost statistical significance in multivariable-adjusted analyses. Intrinsic rTKI resistance was independently associated with inferior subsequent PFS (hazard ratio [HR]: 1.79; 95% CI, 1.15-3.62; p=0.015) and OS (HR: 6.54; 95% CI, 3.01-14.20; p<0.001). Limitations are the retrospective design, limited numbers of cases, and residual confounding factors. CONCLUSIONS The sequence therapies rTKI-EV and rTKI-rTKI may be equally efficacious in terms of PFS and response rate, whereas a tendency towards superior survival was observed for the rTKI-EV sequence. These data, particularly the potential benefit of an early change of mode of action, need confirmation in randomised comparative trials.

Prostate Specific Antigen Density to Predict Prostate Cancer Upgrading in a Contemporary Radical Prostatectomy Series: A Single Center Experience

PURPOSE We investigated the value of pretreatment prostate specific antigen density to predict Gleason score upgrading in light of significant changes in grading routine in the last 2 decades. MATERIALS AND METHODS Of 1,061 consecutive men who underwent radical prostatectomy between 1999 and 2004, 843 were eligible for study. Prostate specific antigen density was calculated and a cutoff for highest accuracy to predict Gleason upgrading was determined using ROC curve analysis. The predictive accuracy of prostate specific antigen and prostate specific antigen density to predict Gleason upgrading was evaluated using ROC curve analysis based on predicted probabilities from logistic regression models. RESULTS Prostate specific antigen and prostate specific antigen density predicted Gleason upgrading on univariate analysis (as continuous variables OR 1.07 and 7.21, each p <0.001) and on multivariate analysis (as continuous variables with prostate specific antigen density adjusted for prostate specific antigen OR 1.07, p <0.001 and OR 4.89, p = 0.037, respectively). When prostate specific antigen density was added to the model including prostate specific antigen and other Gleason upgrading predictors, prostate specific antigen lost its predictive value (OR 1.02, p = 0.423), while prostate specific antigen density remained an independent predictor (OR 4.89, p = 0.037). Prostate specific antigen density was more accurate than prostate specific antigen to predict Gleason upgrading (AUC 0.61 vs 0.57, p = 0.030). CONCLUSIONS Prostate specific antigen density is a significant independent predictor of Gleason upgrading even when accounting for prostate specific antigen. This could be especially important in patients with low risk prostate cancer who seek less invasive therapy such as active surveillance since potentially life threatening disease may be underestimated. Further studies are warranted to help evaluate the role of prostate specific antigen density in Gleason upgrading and its significance for biochemical outcome.

Increased EZH2 protein expression is associated with invasive urothelial carcinoma of the bladder

OBJECTIVES Elevated polycomb group protein Enhancer of Zest Homolog 2 (EZH2) expression has been associated with progression to more advanced disease in a variety of malignancies. We examined EZH2 protein expression levels in bladder tissue specimens from patients with urothelial carcinoma (UC) and investigated the relationship between EZH2 protein expression and clinical outcomes. MATERIALS AND METHODS Tissue microarrays (TMAs) were constructed using bladder tissue specimens from radical cystectomies performed for UC at our institution between 1994 and 2002. EZH2 expression was measured by immunohistochemistry and scoring was based on percentage and intensity of positive nuclear staining. A receiver operating curve (ROC) was generated to differentiate cancerous from benign lesions using EZH2 protein scores. Recurrence-free survival was estimated using the Kaplan-Meier approach with log-rank test. A multivariate Cox proportional hazards model was used to assess independent contributions. RESULTS A total of 454 TMA specimen spots from 81 patients were evaluated. EZH2 protein levels in invasive high grade UC were significantly elevated compared with adjacent benign urothelium, noninvasive low grade UC, and CIS. EZH2 protein levels were also significantly increased in CIS and noninvasive low grade UC compared with adjacent benign urothelium. We found no association between EZH2 protein expression and clinical outcomes following radical cystectomy in our cohort of patients. CONCLUSION EZH2 overexpression is a common event in UC of the bladder. Elevated EZH2 protein levels are associated with more aggressive bladder cancer, including invasive UC. EZH2 may therefore serve as a useful biomarker for UC.

Evaluation of Colon Cancer–Specific Antigen 2 as a Potential Serum Marker for Colorectal Cancer

Purpose: A blood test to detect colon cancer at a preventable stage would represent a major advancement. We have previously identified colon cancer–specific markers using focused proteomics analysis of nuclear structural proteins. Two of these markers, colon cancer–specific antigen (CCSA)-3 and CCSA-4, have been developed into blood-based markers that are able to distinguish individuals with colorectal cancer from those without. CCSA-2 is a distinct novel colon cancer marker identified using focused proteomics. Experimental Design: Using an indirect ELISA on serum samples obtained from two institutions, we evaluated CCSA-2 as a serum-based colon cancer marker. A total of 111 serum samples from individuals who underwent colonoscopy and were subsequently diagnosed as either being normal or having hyperplastic polyps, nonadvanced adenomas, advanced adenomas, and colorectal cancer were evaluated. A diverse control population that consisted of 125 serum samples was also included in this study. Results: Receiver operating characteristic analyses were used to measure the sensitivity and specificity of CCSA-2. CCSA-2 at a cutoff of 10.8 μg/mL has overall specificity of 78.4% [95% confidence interval (95% CI), 67.3-87.1%] and sensitivity of 97.3% (95% CI, 85.8-99.5%) in separating individuals with advanced adenomas and colorectal cancer from normal, hyperplastic, and nonadvanced adenoma populations. The receiver operating characteristic curve for CCSA-2 has an area under the curve of 0.90 (95% CI, 0.83-0.95). Conclusion: Our initial study shows that CCSA-2 is a potential serum-based marker for colon cancer detection with high sensitivity and specificity.

Intrinsic resistance to tyrosine kinase inhibitors is associated with poor clinical outcome in metastatic renal cell carcinoma

BackgroundData on sequential therapy in patients with metastatic renal cell carcinoma (mRCC) and intrinsic resistance to receptor tyrosine kinase inhibitor (rTKI) treatment remains vague.MethodsWe retrospectively studied treatment characteristics and outcome of mRCC patients refractory to first rTKI therapy.ResultsThirty-five mRCC patients (male, 18; female, 11) with primary resistance to first rTKI therapy (sunitinib, n = 28; sorafenib, n = 7) and a median treatment interval of 2.4 months (1 - 4.6) were identified. In 22 patients, progressive disease (PD) was determined by a new metastatic lesion. Of these, 16 patients received subsequent therapy with 12 patients remaining refractory and 4 patients achieving disease stabilization. In 13 patients continuous growth of existing metastatic lesions determined PD. Of these, 9 received sequential therapy with 6 achieving disease stabilization. Altogether, 25 patients were treated sequentially (rTKI: n = 15; mTOR-inhibitor: n = 10) and achieved a median PFS of 3.2 months (range, 1-16.6). Fifteen patients failed to respond to either line of therapy. Disease control was not associated with type of subsequent therapy. Median OS was 14.9 months (CI: 5.5-24.4).ConclusionIntrinsic resistance to rTKI is associated with a low chance of response to sequential therapy and a poor prognosis in mRCC patients.

Long-term oncological and continence outcomes after laparoscopic radical prostatectomy: a single-centre experience

Study Type – Therapy (case series)