Brian J. Miles

OPTIMAL COMBINATIONS OF SYSTEMATIC SEXTANT AND LATERALLY DIRECTED BIOPSIES FOR THE DETECTION OF PROSTATE CANCER

PURPOSE The standard sextant protocol for obtaining transrectal ultrasound guided biopsy of the prostate has been shown to underestimate the presence of prostate cancer. Studies have demonstrated an increased cancer detection rate with additional laterally directed biopsies. We compared the sensitivity of individual biopsy cores and evaluated combinations of these cores to identify an optimal biopsy strategy. MATERIALS AND METHODS A total of 396 consecutive patients underwent biopsy of the lateral peripheral zone in addition to standard sextant biopsy. The cancer detection rate for each biopsy core was calculated. The sensitivity of different combinations of biopsy cores was compared with those of standard sextant biopsies and with a 12 core biopsy protocol that combined the standard sextant biopsy with a complete set of laterally directed cores. RESULTS Cancer was detected in 160 of 396 (40.3%) patients. Of the possible combinations of biopsy cores a strategy that included laterally directed cores at the base, mid gland and apex of the prostate with mid lobar base and apical cores detected 98.5% of cancers. The detection rate of this 10 core biopsy regimen was significantly better than that of the standard sextant protocol (p < or =0.001), and was equivalent to that of the 12 core regional biopsy (p > or =0.302). CONCLUSIONS The standard sextant protocol failed to detect a large proportion of cancers located laterally in the peripheral zone. A 10 core biopsy regimen that combined laterally directed cores at the base, mid gland and apex of the prostate with mid lobar biopsy cores at the base and apex maximizes the sensitivity of transrectal ultrasound guided systematic biopsy.

Optimized microvessel density analysis improves prediction of cancer stage from prostate needle biopsies

OBJECTIVES Clinical staging of prostate cancer is inaccurate, often with significant upstaging on final pathologic review. We previously demonstrated the ability to predict extraprostatic extension of cancer by use of the Gleason score and serum prostate-specific antigen (PSA) measurements. Herein we present an interim analysis of data from an ongoing multi-institutional study to determine the predictive power of an enhancement of microvessel density analysis in combination with Gleason score and serum PSA to predict extraprostatic extension. METHODS We evaluated a total of 186 randomly selected biopsy samples and matched totally embedded radical prostatectomy samples with preoperative PSA concentrations and patient demographics. Gleason score and optimized microvessel density (OMVD) were determined from the needle biopsy samples; pathologic stage was verified by independent review of the radical prostatectomy samples. An automated digital image analysis system measured microvessel morphology and calculated the OMVD in the biopsy samples (Biostage; Bard Diagnostic Sciences, Seattle, Wash). RESULTS Prediction of extraprostatic extension was increased significantly when OMVD analysis was added to Gleason score and serum PSA concentration (P = 0.003). CONCLUSIONS Optimized microvessel density analysis significantly increases the ability to predict extraprostatic extension of cancer preoperatively when combined with Gleason score and serum PSA concentration. This method appears to be a useful tool that can assist with treatment decisions in selected patients.

Sildenafil citrate after radical retropubic prostatectomy

PURPOSE Erectile dysfunction continues to be a significant problem for men after radical retropubic prostatectomy despite nerve sparing techniques. Sildenafil citrate (Viagra) has proved effective for erectile dysfunction in many men. We determine the efficacy of sildenafil in men with erectile dysfunction after radical retropubic prostatectomy and examine variables that may impact the response to treatment. MATERIALS AND METHODS A total of 84 men were prescribed sildenafil after radical retropubic prostatectomy and asked to complete a series of questionnaires, including the International Index of Erectile Function (IIEF), on erectile function before and after sildenafil administration. The importance of factors, such as patient age, time since surgery, degree of cavernous nerve sparing, preoperative prostate specific antigen, Gleason score, clinical and pathological stage, and baseline postoperative erectile function, was examined. RESULTS Of the 84 patients 45 (53%) had improved erections and 34 (40%) had improved ability for intercourse while taking sildenafil. Mean IIEF score for the erectile function domain increased from 9 to 14 (p <0.001). Orgasmic function (p = 0.004) and intercourse satisfaction (p = 0.009) also significantly improved. The degree of nerve sparing and baseline postoperative erectile dysfunction had a significant impact on the ability of sildenafil to improve erectile function (p = 0.010 and p <0.001, respectively) and total IIEF questionnaire responses (p = 0.031 and p <0.001, respectively). Age and pathological stage also appeared to have a significant effect. CONCLUSIONS Sildenafil improved erectile function and the ability to have intercourse in more than half of men after radical retropubic prostatectomy. Baseline postoperative erectile function, which is dependent on the degree of nerve sparing technique, significantly impacts the likelihood that patients will respond to sildenafil.

Global Evaluative Assessment of Robotic Skills: Validation of a Clinical Assessment Tool to Measure Robotic Surgical Skills

PURPOSE We developed and validated a standardized assessment tool for robotic surgical skills, and report its usefulness, reliability and construct validity in a clinical setting. MATERIALS AND METHODS The Global Evaluative Assessment of Robotic Skills is a tool developed by deconstructing the fundamental elements of robotic surgical procedures in consultation with expert robotic surgeons. Surgical performance was assessed during robot-assisted laparoscopic prostatectomy on a 5-point anchored Likert scale across 6 domains. An overall performance score was derived by summing the ratings in each domain. Expert surgeons and postgraduate year 4 to 6 urology residents were evaluated to determine construct validity. Assessments were completed by the attending surgeon, a trained observer and the operator. RESULTS A total of 29 evaluations of 25 trainees and 4 attending surgeons were completed. Experts scored significantly higher on the assessment than novice operators (p = 0.004). Postgraduate year 4 and 5 residents scored significantly lower than the expert group (p <0.05) while no difference was observed between mean performance scores of postgraduate year 6 trainees and attending surgeons (p >0.05). The internal consistency of the assessment tool was excellent (Cronbachs α = 0.90 to 0.93). The overall assessment score ICC among raters was 0.80 (95% CI 0.65-0.90). CONCLUSIONS The Global Evaluative Assessment of Robotic Skills is simple to administer and able to differentiate levels of robotic surgical expertise. This standardized assessment tool shows excellent consistency, reliability and validity. Further study is warranted to evaluate its usefulness for surgical education and the establishment of competency in robotic surgery.

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

The PI3-K-Akt pathway plays a central role in the development and progression of prostate cancer and other malignancies. We review original studies and summarize relevant sections of previous reviews concerning the relationships between abnormalities in the PI3-K-Akt pathway and prostate cancer progression. We discuss laboratory and clinical data that indicate gene perturbation and dysregulation of PI3-K-Akt pathway is common in prostate cancer and other malignancies. We further discuss the critical role of the PI3-K-Akt pathway in the oncogenic signaling network and provide examples that establish the PI3-K-Akt pathway as a focal point for the future development of informative biomarkers and effective therapies for prostate cancer.

A Critique of the Decision Analysis for Clinically Localized Prostate Cancer

The question of when to choose surgery over watchful waiting for treatment of clinically localized prostate cancer is difficult. Recently, the Prostate Patient Outcomes Research Team (PORT) published a decision analysis that promoted watchful waiting as a reasonable alternative to invasive treatment for many men with localized prostatic carcinoma. Criticisms were leveled at the analysis itself, its structure, and especially the probabilities and utilities used in the model. We reexamine the PORT decision analysis. Structural sensitivity of the model was conducted, as were multi-way analyses incorporating data more recent than those used in the PORT analysis. The model structure is concluded to be sound and reasonable given the available literature on prostate cancer progression. However, recent data suggest that some probabilities used in the PORT analysis may be understated, causing life expectancy for surgical treatment to be understated. Using these recent data, the decision to operate on all grades of prostate cancer is strongly supported. This finding contradicts that of the original PORT analysis, which suggested that surgery would decrease quality-adjusted life expectancy for patients with well differentiated lesions. Ethical considerations aside, a clinical trial, such as the Prostate Cancer Intervention Versus Observation Trial, would help to establish reliable progression rates. Also, additional quality of life studies with actual prostatic cancer patients are needed for accurate decision making. Decision scientists and academic urologists should collaborate on model refinement and subsequent analyses.

Cancer-Related Axonogenesis and Neurogenesis in Prostate Cancer

Purpose: Perineural invasion is the only interaction between cancer cells and nerves studied to date. It is a symbiotic relationship between cancer and nerves that results in growth advantage for both. In this article, we present data on a novel biological phenomenon, cancer-related axonogenesis and neurogenesis. Experimental Design: We identify spatial and temporal associations between increased nerve density and preneoplastic and neoplastic lesions of the human prostate. Results: Nerve density was increased in cancer areas as well as in preneoplastic lesions compared with controls. Two- and three-dimensional reconstructions of entire prostates confirmed axonogenesis in human tumors. Furthermore, patients with prostate cancer had increased numbers of neurons in their prostatic ganglia compared with controls, corroborating neurogenesis. Finally, two in vitro models confirmed that cancer cells, particularly when interacting with nerves in perineural invasion, induce neurite outgrowth in prostate cancer. Neurogenesis is correlated with features of aggressive prostate cancer and with recurrence in prostate cancer. We also present a putative regulatory mechanism based on semaphorin 4F (S4F). S4F is overexpressed in cancers cells in the perineural in vitro model. Overexpression of S4F in prostate cancer cells induces neurogenesis in the N1E-115 neurogenesis assay and S4F inhibition by small interfering RNA blocks this effect. Conclusions: This is the first description of cancer-related neurogenesis and its putative regulatory mechanism.

Phase I/II trial evaluating combined radiotherapy and in situ gene therapy with or without hormonal therapy in the treatment of prostate cancer--a preliminary report.

PURPOSE To report the preliminary results of a Phase I/II study combining radiotherapy and in situ gene therapy (adenovirus/herpes simplex virus thymidine kinase gene/valacyclovir) with or without hormonal therapy in the treatment of prostate cancer. METHODS AND MATERIALS Arm A: low-risk patients (T1-T2a, Gleason score <7, pretreatment PSA <10) were treated with combined radio-gene therapy. A mean dose of 76 Gy was delivered to the prostate with intensity-modulated radiotherapy. Arm B: high-risk patients (T2b-T3, Gleason score >or=7, pretreatment PSA >or=10) were treated with combined radio-gene therapy and hormonal therapy. Hormonal therapy was comprised of a 4-month leuprolide injection and 2-week use of flutamide. Arm C: Stage D1 (positive pelvic lymph node) patients received the same regimen as Arm B, with the additional 45 Gy to the pelvic lymphatics. Treatment-related toxicity was assessed using Cancer Therapy Evaluation Program common toxicity score and Radiation Therapy Oncology Group (RTOG) toxicity score. RESULTS Thirty patients (13 in Arm A, 14 in Arm B, and 3 in Arm C) completed the trial. Median follow-up was 5.5 months. Eleven patients (37%) developed flu-like symptoms (Cancer Therapy Evaluation Program Grade 1) of fatigue and chills/rigors after gene therapy injection but recovered within 24 h. Four patients (13%) and 2 patients (7%) developed Grade 1 and 2 fever, respectively. There was no patient with weight loss. One patient in Arm B developed Grade 3 elevation in liver enzyme, whereas 11 and 2 patients developed Grade 1 and 2 abnormal liver function tests. There was no Grade 2 or above hematologic toxicity. Three patients had transient rise in creatinine. There was no RTOG Grade 3 or above lower gastrointestinal toxicity. Toxicity levels were as follows: 4 patients (13%), Grade 2; 6 patients (20%), Grade 1; and 20 patients (67%), no toxicity. There was 1 patient with RTOG Grade 3 genitourinary toxicity, 12 patients (40%) with Grade 2, 8 patients (27%) with Grade 1, and 9 patients (30%) with no toxicity. No patient dropped out from the trial or had to withhold treatment because of severe toxicity. CONCLUSIONS This is the first trial of its kind in the field of prostate cancer that aims to expand the therapeutic index of radiotherapy by combining in situ gene therapy. Initial experience has demonstrated the safety of this approach. There is no added toxicity to each therapy used alone. Long-term follow-up and larger cohort studies are warranted to evaluate long-term toxicity and efficacy.

Prostate-Specific Antigen Response and Systemic T Cell Activation After In Situ Gene Therapy in Prostate Cancer Patients Failing Radiotherapy

In an extended phase I/II study we evaluated 36 prostate cancer patients with local recurrence after radiotherapy who received single or repeated cycles of replication-deficient adenoviral vector (ADV)-mediated herpes simplex virus-thymidine kinase (HSV-tk) plus ganciclovir (GCV) in situ gene therapy with respect to serum PSA levels, alterations in immune cells, and numbers of apoptotic cells in needle biopsies. An initial cycle of HSV-tk plus GCV gene therapy caused a significant prolongation of the mean serum PSA-doubling time (PSADT) from 15.9 to 42.5 months (p = 0.0271) and in 28 of the injected patients (77.8%) there was a mean PSA reduction (PSAR) of 28%. It took a mean of 8.5 months for the PSA to return to the initial PSA (TR-PSA) value. A repeated cycle of gene therapy failed to significantly extend PSADT but did result in significant increases in PSAR (29.4%) and TR-PSA (10.5 months). Moderately increased serum adenovirus antibody titers were generally observed 2 weeks after initial vector injection. Also at this time there was a statistically significant increase in the mean percent of CD8(+) T cells positive for the HLA-DR marker of activation in peripheral blood (p = 0.0088). Studies using prostate biopsies obtained at the same time point demonstrated that vector DNA was detectable by PCR in most samples yet all patients remained positive for prostate cancer in at least one biopsy core. Further analysis demonstrated a correlation between the level of CD8(+) cells and the number of apoptotic cells in biopsies containing cancer cells (p = 0.042). We conclude that repeated cycles of in situ HSV-tk plus GCV gene therapy can be administered to prostate cancer patients who failed radiotherapy and have a localized recurrence. Biological responses to this experimental therapy including increases in PSADT, PSAR, and TR-PSA, and activated CD8(+) T cells present in the peripheral blood, were demonstrated. Interestingly, the density of CD8(+) cells in posttreatment biopsies correlated with the number of apoptotic cells.

Entertainment Education for Prostate Cancer Screening: A Randomized Trial among Primary Care Patients with Low Health Literacy

OBJECTIVE To evaluate an entertainment-based patient decision aid for prostate cancer screening among patients with low or high health literacy. METHODS Male primary care patients from two clinical sites, one characterized as serving patients with low health literacy (n=149) and the second as serving patients with high health literacy (n=301), were randomized to receive an entertainment-based decision aid for prostate cancer screening or an audiobooklet-control aid with the same learner content but without the entertainment features. Postintervention and 2-week follow-up assessments were conducted. RESULTS Patients at the low-literacy site were more engaged with the entertainment-based aid than patients at the high-literacy site. Overall, knowledge improved for all patients. Among patients at the low-literacy site, the entertainment-based aid was associated with lower decisional conflict and greater self-advocacy (i.e., mastering and obtaining information about screening) when compared to patients given the audiobooklet. No differences between the aids were observed for patients at the high-literacy site. CONCLUSION Entertainment education may be an effective strategy for promoting informed decision making about prostate cancer screening among patients with lower health literacy. PRACTICE IMPLICATIONS As barriers to implementing computer-based patient decision support programs decrease, alternative models for delivering these programs should be explored.